Schizophrenic Disorder Treatment using Combination Therapy

ABSTRACT

The present specification disclose a combined therapy comprising one or more activators of an alpha-7 nicotinic acetylcholine receptor activity having 5-HT3 receptor inhibitory activity and one or more activators of 5-HT3 receptor activity for use in treating a schizophrenic disorder as well as methods of treating a schizophrenic disorder by administering a combined therapy comprising one or more activators of an alpha-7 nicotinic acetylcholine receptor activity having 5-HT3 receptor inhibitory activity and one or more activators of 5-HT3 receptor activity.

This application is a 35 U.S.C. § 371 U.S. national stage patentapplication which claims the benefit of priority and is entitled to thefiling date of International Patent Application PCT/EP2020/079651, filedOct. 21, 2020, an international patent application which claims thebenefit of priority and is entitled to the filing date pursuant of 35U.S.C. § 119(e) of U.S. Provisional Patent Application 62/924,114, filedOct. 21, 2019, the content of each of which is hereby incorporated byreference in its entirety.

A schizophrenic disorder is generally considered to be a syndrome,probably a group of mental disorders, involving a breakdown in therelation between thought, emotion, and behavior leading to diversedisturbances in cognition, perception, reality testing, actions,feelings, mood, interpersonal relations, social interaction, andoccupational function. A chronic, severe, and disabling psychiatricdisorder, a schizophrenic disorder affects 0.5% to 1% of the globalpopulation. Both men and women are at equal risk in developing thisbrain disorder, which occurs at similar rates in all ethnic groupsaround the world. Disease onset shows a gender-bias with men usuallyshowing symptoms between their late teens and early twenties and womenusually develop symptoms during their mid-twenties to early thirties.

A schizophrenic disorder affects people differently and symptoms canvary from person to person. Some people can have many symptoms, whileothers may only have a few. The clinical features of a schizophrenicdisorder can be clustered into three symptom groups, positive symptoms,negative symptom and cognitive symptoms. Positive symptoms areclassified as fixed, false feelings or behaviors involving real-lifesituations that could be true but are simply manifestations ofpsychosis, such as, e.g., delusions, hallucinations, paranoia, thoughtdisorders (disorganized thinking, speech or behavior, neologism) andmovement disorders (clumsy, uncoordinated, repetitious movements,catatonia). Negative symptoms are classified as deficits or reductionsin normal emotion and behavior, such as, e.g., affective disturbances(immobile expression, monotonous voice), reduced interest or lack ofpleasure in everyday activities (anhedonia, like depression), lack ofmotivation (avolition), decreased ability to initiate and sustainplanned activity, poverty of speech (alogia), infrequent speech (evenwhen forced to interact), and social withdrawal. Cognitive symptoms areclassified as deficits in the mental processes of comprehension,judgement, memory and reasoning, such as, e.g., problems in selectiveattention, working memory, executive function, episodic memory, languagecomprehension and social-emotional processing. The disease is alsoassociated with some quantitative abnormalities in brain structure,e.g., enlarged ventricles and decreased temporal lobe volume, but theseabnormalities are not specific to a schizophrenic disorder. While theemergence of positive symptoms in early adulthood is the most strikingclinical feature, cognitive deficits are a core feature of the disorder,are present prior to the onset of psychosis and are the single bestpredictor of long-term functional outcome.

There is currently no cure for a schizophrenic disorder and individualsdiagnosed with this mental illness require chronic treatment. Theprimary treatment of a schizophrenic disorder is antipsychoticmedications, often in combination with psychological and socialsupports. Clinical studies have shown that early treatment usingantipsychotic drugs can be effective in managing symptoms of psychosisbefore serious complications develop and in improving the long-termoutlook of such treated individuals. For this reason, antipsychotic drugtreatment is considered a key component of a schizophrenic disordertreatment and is recommended by the National Institute of Health andCare Excellence (NICE), the American Psychiatric Association, and theBritish Society for Psychopharmacology.

Currently, all approved antipsychotic drugs work relatively the sameway, by antagonizing D2 dopamine receptors. Unfortunately,dopaminergic-based antipsychotic drugs are effective only in managingthe positive symptoms of a schizophrenic disorder. Such medications havelittle to no effect on negative or cognitive symptoms, which are themost disabling impairments to an individual in leading a normal life,and that most affect their quality of living. The ineffectiveness ofdopaminergic-based antipsychotic drugs is a driving factor for the poorsocial and functional outcomes that bring high personal and societalcosts to an individual suffering from a schizophrenic disorder. Despiteconsiderable recent effort by the pharmaceutical industry, no novelmechanisms have yet been approved for addressing the cognitive andnegative symptoms associated with a schizophrenic disorder and therehave been many late-stage failures. It is, therefore, of paramountimportance to identify new therapeutic approaches for the treatment of aschizophrenic disorder.

The present specification discloses a combination therapy comprising analpha-7 nicotinic acetylcholine receptor agonist having 5-HT₃ receptorinhibitory activity and a serotonin agonist useful in the effectivetreatment of a schizophrenic disorder. A disclosed serotonin agonist mayoptionally further include an alpha-7 nicotinic acetylcholine receptoragonistic activity. Such combination therapy successfully mitigatesgastrointestinal side effects to facilitate and enable long-termtreatment that effectively ameliorates positive, negative and cognitivesymptoms of this mental illness.

SUMMARY

Aspects of the present specification disclose methods of treating aschizophrenic disorder by administering a combined therapy comprisingone or more activators of an alpha-7 nicotinic acetylcholine receptoractivity having 5-HT₃ receptor inhibitory activity and one or moreactivators of 5-HT₃ receptor activity.

Aspects of the present specification disclose a combined therapy for usein treating a schizophrenic disorder, the combined therapy comprisingone or more activators of an alpha-7 nicotinic acetylcholine receptoractivity having 5-HT₃ receptor inhibitory activity and one or moreactivators of 5-HT₃ receptor activity.

Aspects of the present specification disclose use of a combined therapyin treating a schizophrenic disorder, the combined therapy comprisingone or more activators of an alpha-7 nicotinic acetylcholine receptoractivity having 5-HT₃ receptor inhibitory activity and one or moreactivators of 5-HT₃ receptor activity.

Aspects of the present specification disclose use of one or moreactivators of an alpha-7 nicotinic acetylcholine receptor activityhaving 5-HT₃ receptor inhibitory activity and one or more activators of5-HT₃ receptor activity in the manufacture of a medicament for treatinga schizophrenic disorder.

Aspects of the present specification disclose methods of treating aschizophrenic disorder by administering a combined therapy comprisingone or more alpha-7 nicotinic acetylcholine receptor agonist having5-HT₃ receptor antagonistic activity and one or more 5-HT₃ receptoragonists.

Aspects of the present specification disclose a combined therapy for usein treating a schizophrenic disorder, the combined therapy comprisingone or more alpha-7 nicotinic acetylcholine receptor agonist having5-HT₃ receptor antagonistic activity and one or more 5-HT₃ receptoragonists.

Aspects of the present specification disclose use of a combined therapyin treating a schizophrenic disorder, the combined therapy comprisingone or more alpha-7 nicotinic acetylcholine receptor agonist having5-HT₃ receptor antagonistic activity and one or more activators of 5-HT₃receptor activity.

Aspects of the present specification disclose use of one or more alpha-7nicotinic acetylcholine receptor agonist having 5-HT₃ receptorantagonistic activity and one or more activators of 5-HT₃ receptoractivity in the manufacture of a medicament for treating a schizophrenicdisorder.

Aspects of the present specification disclose methods of treating aschizophrenic disorder by administering a combined therapy comprisingone or more alpha-7 nicotinic acetylcholine receptor agonist having5-HT₃ receptor inverse agonistic activity and one or more 5-HT₃ receptoragonists.

Aspects of the present specification disclose a combined therapy for usein treating a schizophrenic disorder, the combined therapy comprisingone or more alpha-7 nicotinic acetylcholine receptor agonist having5-HT₃ receptor inverse agonistic activity and one or more 5-HT₃ receptoragonists.

Aspects of the present specification disclose use of a combined therapyin treating a schizophrenic disorder, the combined therapy comprisingone or more alpha-7 nicotinic acetylcholine receptor agonist having5-HT₃ receptor inverse agonistic activity and one or more activators of5-HT₃ receptor activity.

Aspects of the present specification disclose use of one or more alpha-7nicotinic acetylcholine receptor agonist having 5-HT₃ receptor inverseagonistic activity and one or more activators of 5-HT₃ receptor activityin the manufacture of a medicament for treating a schizophrenicdisorder.

DETAILED DESCRIPTION

As with all family members, the alpha-7 nicotinic acetylcholine receptor(α7 nAChR) is considered a cholinergic receptor because it responds tothe neurotransmitter acetylcholine. α7 nAChR are pentameric polypeptidesconsisting entirely of α7 subunits [i.e., (α7)₅ stoichiometry]. Locatedin the brain, α7 nAChR appear to be critical for memory, working memory,learning, and attention.

Agonists of the α7 nAChR were developed as potential therapeutic for usein alleviating the cognitive impairment associated with schizophreniadue to their positive effects on neurocognition. However, to date allsuch drug candidates have failed during clinical trials, typically atphase 2 or 3 (e.g., Abbvie, Forum Pharmaceuticals, Roche). Although thesafety profile of these α7 nAChR agonists was generally good, oneadverse outcome associated with their use was gastrointestinal (GI) sideeffects including a reduction in gut transit and constipation driven bythe 5-HT3 receptor antagonistic activity of these α7 nAChR agonists.

5-hydroxytryptamine (5-HT) or serotonin is a monoamine neurotransmitterthat mediates an individual's perceptions of resources, having havediverse effects on mood, anxiety, sleep, appetite, temperature, eatingbehavior, sexual behavior, movements, and gastrointestinal motility.This neurotransmitter is produced primarily in the enteric nervoussystem located in the gastrointestinal tract but is also found in thecentral nervous system (CNS), specifically in the Raphe nuclei locatedin the brainstem.

Serotonin mediates its action through serotonin receptors (5-HTreceptors). Upon binding of its ligand, serotine receptors modulate therelease of many neurotransmitters, including glutamate, GABA, dopamine,epinephrine/norepinephrine, and acetylcholine, as well as many hormones,including oxytocin, prolactin, vasopressin, cortisol, corticotropin, andsubstance P. Mediating both excitatory and inhibitory neurotransmission,serotonin receptors influence various biological and neurologicalprocesses such as aggression, anxiety, appetite, cognition, learning,memory, mood, nausea, sleep, and thermoregulation. Divided into sevenfamilies, serotonin receptors are found in the central and peripheralnervous systems.

Except for the serotonin type 3 (5-HT₃) receptor, all other 5-HTreceptors are G-protein-coupled receptors that activate an intracellularsecond messenger cascade.

The 5-HT₃ receptor belongs to the Cys-loop superfamily of ligand-gatedion channels (LGICs) that includes receptors for acetylcholine,γ-aminobutyric acid-type-A (GABA)A and glycine and therefore differsstructurally and functionally from all other 5-HT receptors. This ionchannel is cation-selective and mediates rapid neuronal depolarizationand excitation predominantly carried by an inward current of sodiumand/or potassium ions. The 5-HT₃ receptor is found many regions of theCNS including the entorhinal cortex, hippocampus CA1 area, amygdala,substantia nigra, and brainstem, and the peripheral nervous systems andmediates a variety of physiological functions. On a cellular level, ithas been shown that postsynaptic 5-HT₃ receptors mediate fast excitatorysynaptic transmission in neocortical interneurons, amygdala, andhippocampus, and in the visual cortex. 5-HT₃ receptors are also presenton presynaptic nerve terminals. The 5-HT₃ receptors also play animportant role in the enteric nervous system.

As with other ligand gated ion channels, the functional 5-HT₃ receptorforms a pentamer of five pseudo-symmetrically arranged subunitssurrounding a central ion conducting pore. Currently five 5-HT₃ receptorsubunits are known (5-HT3A to 5-HT3E). A functional channel may becomposed of five identical 5-HT3A subunits (homopentameric) or a mixtureof 5-HT3A and one of the other four 5-HT3B, 5-HT₃c, 5-HT3D, or 5-HT3Esubunits (heteropentameric). Each subunit comprises an extracellularN-terminal domain which comprises the orthosteric ligand-binding site; atransmembrane domain consisting of four interconnected alpha helices(M1-M4), with the extracellular M2-M3 loop involved in the gatingmechanism; a large cytoplasmic domain between M3 and M4 involved inreceptor trafficking and regulation; and a short extracellularC-terminus. Whereas extracellular domain is the site of action ofagonists and competitive antagonists, the transmembrane domain containsthe central ion pore, receptor gate, and principle selectivity filterthat allows ions to cross the cell membrane.

Besides its endogenous ligand serotonin, the downstream activitiesmediated by 5-HT₃ receptors can be modulated by exogenous compounds suchas, e.g., a 5-HT₃ receptor agonist, a 5-HT₃ receptor antagonist or a5-HT₃ receptor inverse agonist. 5-HT₃ receptor agonists and inverseagonists do not appear to be of any clinical interests, being usedprimarily as preclinical reagents. On the other hand, 5-HT₃ receptorantagonists are potent antiemetics used for prevention of postsurgicalor chemotherapy induced nausea and vomiting and for some agents astherapy of diarrhea-predominant irritable bowel syndrome. The antiemeticeffects appear to be the result of both central and peripheralinhibition of serotonin activity, with a decrease in vagal activity aswell as interruption of pathways in the chemoreceptor trigger zone andsolitary tract nucleus of the brainstem.

The present specification discloses in part, methods of treating aschizophrenic disorder. In one embodiment, a method of treating aschizophrenic disorder disclosed herein comprises, consists essentiallyof, or consists of administering a combined therapy comprising,consisting essentially of, or consisting of one or more activators of analpha-7 nicotinic acetylcholine receptor activity having 5-HT₃ receptorinhibitory activity and one or more activators of 5-HT₃ receptoractivity. In one embodiment, a method of treating a schizophrenicdisorder disclosed herein comprises, consists essentially of, orconsists of administering a combined therapy comprising, consistingessentially of, or consisting of one or more alpha-7 nicotinicacetylcholine receptor agonists having 5-HT₃ receptor antagonisticactivity and one or more 5-HT₃ receptor agonists. In one embodiment, amethod of treating a schizophrenic disorder disclosed herein comprises,consists essentially of, or consists of administering a combined therapycomprising, consisting essentially of, or consisting of one or morealpha-7 nicotinic acetylcholine receptor agonists having 5-HT₃ receptorinverse agonistic activity and one or more 5-HT₃ receptor agonists. In apreferred embodiment, a method of treating a schizophrenic disorderdisclosed herein comprises, consists essentially of, or consists ofadministering a combined therapy comprising, consisting essentially of,or consisting of Tropisetron and Varenicline. In the embodimentsdisclosed above, an amount of an activators of an alpha-7 nicotinicacetylcholine receptor activity having 5-HT₃ receptor inhibitoryactivity, an activator of 5-HT₃ receptor activity, an alpha-7 nicotinicacetylcholine receptor agonist having 5-HT₃ receptor antagonisticactivity, an alpha-7 nicotinic acetylcholine receptor agonist having5-HT₃ receptor inverse agonistic activity, a 5-HT₃ receptor agonist,Varenicline and/or Tropisetron is a therapeutically effective amount.

The present specification discloses, in part, a combined therapy for usein treating a schizophrenic disorder. In one embodiment, a combinedtherapy comprising, consists essentially of, or consists of one or moreactivators of an alpha-7 nicotinic acetylcholine receptor activityhaving 5-HT₃ receptor inhibitory activity and one or more activators of5-HT₃ receptor activity for use in treating a schizophrenic disorder. Inone embodiment, a combined therapy comprising, consists essentially of,or consists of one or more alpha-7 nicotinic acetylcholine receptoragonists having 5-HT₃ receptor antagonistic activity and one or more5-HT₃ receptor agonists for use in treating a schizophrenic disorder. Inone embodiment, a combined therapy comprising, consists essentially of,or consists of one or more alpha-7 nicotinic acetylcholine receptoragonists having 5-HT₃ receptor inverse agonistic activity and one ormore 5-HT₃ receptor agonists for use in treating a schizophrenicdisorder. In a preferred embodiment, a combined therapy comprising,consists essentially of, or consists of Tropisetron and Varenicline foruse in treating a schizophrenic disorder. In the embodiments disclosedabove, an amount of an activators of an alpha-7 nicotinic acetylcholinereceptor activity having 5-HT₃ receptor inhibitory activity, anactivator of 5-HT₃ receptor activity, an alpha-7 nicotinic acetylcholinereceptor agonist having 5-HT₃ receptor antagonistic activity, an alpha-7nicotinic acetylcholine receptor agonist having 5-HT₃ receptor inverseagonistic activity, a 5-HT₃ receptor agonist, Varenicline and/orTropisetron is a therapeutically effective amount.

The present specification discloses, in part, a combination therapy. Acombination therapy encompasses separate use or administration of afirst composition comprising, consists essentially of, or consists ofone or more activators of 5-HT₃ receptor activity and a secondcomposition comprising, consists essentially of, or consists of one ormore activators of an alpha-7 nicotinic acetylcholine receptor activityhaving 5-HT₃ receptor inhibitory activity or a use or administration ofa single composition comprising, consists essentially of, or consists ofone or more activators of 5-HT₃ receptor activity and one or moreactivators of an alpha-7 nicotinic acetylcholine receptor activityhaving 5-HT₃ receptor inhibitory activity. In an aspect of thisembodiment, a combination therapy encompasses separate use oradministration of a first composition comprising, consists essentiallyof, or consists of one or more 5-HT₃ receptor agonists and a secondcomposition comprising, consists essentially of, or consists of one ormore alpha-7 nicotinic acetylcholine receptor agonists having 5-HT₃receptor antagonistic activity or a use or administration of a singlecomposition comprising, consists essentially of, or consists of one ormore 5-HT₃ receptor agonists and one or more alpha-7 nicotinicacetylcholine receptor agonists having 5-HT₃ receptor antagonisticactivity. In another aspect of this embodiment, a combination therapyencompasses separate use or administration of a first compositioncomprising, consists essentially of, or consists of one or more 5-HT₃receptor agonists and a second composition comprising, consistsessentially of, or consists of one or more alpha-7 nicotinicacetylcholine receptor agonists having 5-HT₃ receptor inverse agonisticactivity or a use or administration of a single composition comprising,consists essentially of, or consists of one or more 5-HT₃ receptoragonists and one or more alpha-7 nicotinic acetylcholine receptoragonists having 5-HT₃ receptor inverse agonistic activity. In apreferred embodiment, a combination therapy encompasses separate use oradministration of a first composition comprising, consists essentiallyof, or consists of Varenicline and a second composition comprisingTropisetron or a use or administration of a single compositioncomprising, consists essentially of, or consists of Varenicline andTropisetron. In the embodiments disclosed above, an amount of aninhibitor of 5-HT3 receptor activity, an activator of 5-HT₃ receptoractivity, an alpha-7 nicotinic acetylcholine receptor agonist having5-HT₃ receptor antagonistic activity, an alpha-7 nicotinic acetylcholinereceptor agonist having 5-HT₃ receptor inverse agonistic activity, a5-HT₃ receptor agonist, Varenicline and/or Tropisetron is atherapeutically effective amount. In all embodiments disclosed above, afirst and second composition can be used or administered sequentially inany order or simultaneously.

In one embodiment, a combination therapy disclosed herein can comprise asingle activator of 5-HT₃ receptor activity and a single activator of analpha-7 nicotinic acetylcholine receptor activity having 5-HT₃ receptorinhibitory activity, a plurality of activators of 5-HT₃ receptoractivity and a single activator of an alpha-7 nicotinic acetylcholinereceptor activity having 5-HT₃ receptor inhibitory activity, a singleactivator of 5-HT₃ receptor activity and a plurality of activators of analpha-7 nicotinic acetylcholine receptor activity having 5-HT₃ receptorinhibitory activity, or a plurality of activators of 5-HT₃ receptoractivity and a plurality of activators of an alpha-7 nicotinicacetylcholine receptor activity having 5-HT₃ receptor inhibitoryactivity. In aspects of this embodiment, a combination therapy cancomprise 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 3-4, 3-5, or 4-5 activatorsof 5-HT₃ receptor activity and a single activator of an alpha-7nicotinic acetylcholine receptor activity having 5-HT₃ receptorinhibitory activity. In other aspects of this embodiment, a combinationtherapy can comprise a single activator of 5-HT₃ receptor activity and1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 3-4, 3-5, or 4-5 activators of analpha-7 nicotinic acetylcholine receptor activity having 5-HT₃ receptorinhibitory activity. In yet other aspects of this embodiment, acombination therapy can comprise 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 3-4,3-5, or 4-5 activators of 5-HT₃ receptor activity and 1-2, 1-3, 1-4,1-5, 2-3, 2-4, 2-5, 3-4, 3-5, or 4-5 activators of an alpha-7 nicotinicacetylcholine receptor activity having 5-HT₃ receptor inhibitoryactivity.

In one embodiment, a combination therapy disclosed herein can comprise asingle 5-HT₃ receptor agonist and a single alpha-7 nicotinicacetylcholine receptor agonist having 5-HT₃ receptor antagonisticactivity, a plurality of 5-HT₃ receptor agonists and a single alpha-7nicotinic acetylcholine receptor agonist having 5-HT₃ receptorantagonistic activity, a single 5-HT₃ receptor agonist and a pluralityof alpha-7 nicotinic acetylcholine receptor agonists having 5-HT₃receptor antagonistic activity, or a plurality of 5-HT₃ receptoragonists and a plurality of alpha-7 nicotinic acetylcholine receptoragonists having 5-HT₃ receptor antagonistic activity. In aspects of thisembodiment, a combination therapy can comprise 1-2, 1-3, 1-4, 1-5, 2-3,2-4, 2-5, 3-4, 3-5, or 4-5 5-HT₃ receptor agonists and a single alpha-7nicotinic acetylcholine receptor agonist having 5-HT₃ receptorantagonistic activity. In other aspects of this embodiment, acombination therapy can comprise a single 5-HT₃ receptor agonist and1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 3-4, 3-5, or 4-5 alpha-7 nicotinicacetylcholine receptor agonists having 5-HT₃ receptor antagonisticactivity. In yet other aspects of this embodiment, a combination therapycan comprise 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 3-4, 3-5, or 4-5 5-HT₃receptor agonists and 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 3-4, 3-5, or4-5 alpha-7 nicotinic acetylcholine receptor agonists having 5-HT₃receptor antagonistic activity.

In one embodiment, a combination therapy disclosed herein can comprise asingle 5-HT₃ receptor agonist and a single alpha-7 nicotinicacetylcholine receptor agonist having 5-HT₃ receptor inverse agonisticactivity, a plurality of 5-HT₃ receptor agonists and a single alpha-7nicotinic acetylcholine receptor agonist having 5-HT₃ receptor inverseagonistic activity, a single 5-HT₃ receptor agonist and a plurality ofalpha-7 nicotinic acetylcholine receptor agonists having 5-HT₃ receptorinverse agonistic activity, or a plurality of 5-HT₃ receptor agonistsand a plurality of alpha-7 nicotinic acetylcholine receptor agonistshaving 5-HT₃ receptor inverse agonistic activity. In aspects of thisembodiment, a combination therapy can comprise 1-2, 1-3, 1-4, 1-5, 2-3,2-4, 2-5, 3-4, 3-5, or 4-5 5-HT₃ receptor agonists and a single alpha-7nicotinic acetylcholine receptor agonist having 5-HT₃ receptor inverseagonistic activity. In other aspects of this embodiment, a combinationtherapy can comprise a single 5-HT₃ receptor agonist and 1-2, 1-3, 1-4,1-5, 2-3, 2-4, 2-5, 3-4, 3-5, or 4-5 alpha-7 nicotinic acetylcholinereceptor agonists having 5-HT₃ receptor inverse agonistic activity. Inyet other aspects of this embodiment, a combination therapy can comprise1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 3-4, 3-5, or 4-5 5-HT₃ receptoragonists and 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 3-4, 3-5, or 4-5 alpha-7nicotinic acetylcholine receptor agonists having 5-HT₃ receptor inverseagonistic activity.

The present specification discloses, in part, an activator of 5-HT₃receptor activity. An activator of 5-HT₃ receptor activity is anymolecule that initiates increases, enhances, or otherwise activates theactivity of a 5-HT₃ receptor. Non-limiting examples of an activator of5-HT₃ receptor activity include a 5-HT₃ receptor agonist.

The present specification discloses, in part, an activator of an alpha-7nicotinic acetylcholine receptor activity having 5-HT₃ receptorinhibitory activity. An activator of an alpha-7 nicotinic acetylcholinereceptor activity having 5-HT₃ receptor inhibitory activity is anymolecule that initiates increases, enhances, or otherwise activates theactivity of an alpha-7 nicotinic acetylcholine receptor that alsoreduces, dampens, prevents or otherwise inhibits the activity of a 5-HT₃receptor. Non-limiting examples of an activator of an alpha-7 nicotinicacetylcholine receptor activity having 5-HT₃ receptor inhibitoryactivity include an alpha-7 nicotinic acetylcholine receptor agonisthaving 5-HT₃ receptor antagonistic activity and an alpha-7 nicotinicacetylcholine receptor agonist having 5-HT₃ receptor inverse agonisticactivity.

The present specification discloses, in part, a 5-HT₃ receptor agonist.A 5-HT₃ receptor agonist is a compound that binds to a 5-HT₃ receptorand activates or provokes the receptor to produce a biological response.A 5-HT₃ receptor agonist disclosed herein can be a full agonist, apartial agonist, a co-agonist or a super-agonist. A 5-HT₃ full receptoragonist bind to and activate a 5-HT₃ receptor with the maximum responsethat an agonist can elicit at the receptor. A 5-HT₃ partial receptoragonist bind and activate a given 5-HT₃ receptor, but elicits onlypartial effect at the receptor relative to a full agonist, even atmaximal receptor occupancy. Although they are agonists, 5-HT₃ receptorpartial agonists can act as a competitive antagonist in the presence ofa 5-HT₃ receptor full agonist, as it competes with the full agonist forreceptor occupancy, thereby producing a net decrease in the receptoractivation as compared to that observed with the full agonist alone A5-HT₃ co-agonist works together with other 5-HT₃ receptor co-agonists toproduce the desired biological response. A 5-HT₃ receptor agonistdisclosed herein can be a 5-HT₃ receptor super-agonist which is capableof producing a greater biological response at that receptor thanserotonin.

A 5-HT₃ receptor agonist disclosed herein can be a pan-agonist or aselective agonist. A 5-HT₃ receptor pan-agonist binds to and elicits abiological response from any 5-HT-3 receptor irrespective of subunitcomposition. A 5-HT₃ receptor selective agonist binds selective to aspecific type of 5-HT₃ receptor, eliciting a biological response of viathese specific 5-HT₃ receptors. For example, a 5-HT₃ selective agonistcan bind to and elicit a biological response from only 5-HT₃homopentameric receptors, or only 5-HT₃ heteropentameric receptors, oronly 5-HT₃ heteropentameric receptors of certain subunit composition,such as, e.g., 5-HT3AC heteropentameric receptors, 5-HT3ADheteropentameric receptors, or 5-HT3AE heteropentameric receptors.

A 5-HT₃ receptor agonist disclosed herein includes, without limitation,an alcohol having 5-HT₃ receptor agonist activity,meta-Chlorophenylbiguanide (1-(3-Chlorophenylbiguanide)), Ibogaine,Phenylbiguanide, a piperazine having 5-HT₃ receptor agonist activity,RS-56812(N-(1-Azabicyclo[2.2.2]octan-3-yl)-2-(1-methylindol-3-yl)-2-oxoacetamide),Serotonin (5-HT), SR-57227 (1-(6-Chloropyridin-2-yl)piperidin-4-amine),SR-57227A (4-Amino-1-(6-chloro-2-pyridyl)-piperidine hydrochloride), atryptamine having 5-HT₃ receptor agonist activity, Varenicline, avolatile gas having 5-HT₃ receptor agonist activity, and YM-31636(2-(1H-imidazol-4-ylmethyl)-8H-indeno[1,2-d]thiazole). Non-limitingexamples of an alcohol having 5-HT₃ receptor agonist activity includebutanol, ethanol, and trichloroethanol. Non-limiting examples of apiperazine having 5-HT₃ receptor agonist activity includebenzylpiperazine, meta-Chlorophenylpiperazine, and quipazine.Non-limiting examples of a tryptamine having 5-HT₃ receptor agonistactivity include 2-methyl-5-hydroxytryptamine, α-Methyltryptamine,5-carboxamidotryptamine, N,N-Dimethyl-5-hydroxytryptamine (Bufotenin),and 5-hydroxy-N,N,N-trimethyltryptammonium (bufotenidine). Non-limitingexamples of a volatile gas having 5-HT₃ receptor agonist activityinclude halothane, isoflurane, toluene, and trichloroethane.

The present specification discloses, in part, an alpha-7 nicotinicacetylcholine receptor agonist. An alpha-7 nicotinic acetylcholinereceptor agonist is a compound that binds to an alpha-7 nicotinicacetylcholine receptor and activates or provokes the receptor to producea biological response. An alpha-7 nicotinic acetylcholine receptoragonist disclosed herein can be a full agonist, a partial agonist, aco-agonist or a super-agonist. An alpha-7 nicotinic acetylcholine fullreceptor agonist bind to and activate a alpha-7 nicotinic acetylcholinereceptor with the maximum response that an agonist can elicit at thereceptor. An alpha-7 nicotinic acetylcholine partial receptor agonistbind and activate a given alpha-7 nicotinic acetylcholine receptor, butelicits only partial effect at the receptor relative to a full agonist,even at maximal receptor occupancy. Although they are agonists, alpha-7nicotinic acetylcholine receptor partial agonists can act as acompetitive antagonist in the presence of a alpha-7 nicotinicacetylcholine receptor full agonist, as it competes with the fullagonist for receptor occupancy, thereby producing a net decrease in thereceptor activation as compared to that observed with the full agonistalone An alpha-7 nicotinic acetylcholine co-agonist works together withother alpha-7 nicotinic acetylcholine receptor co-agonists to producethe desired biological response. An alpha-7 nicotinic acetylcholinereceptor agonist disclosed herein can be a alpha-7 nicotinicacetylcholine receptor super-agonist which is capable of producing agreater biological response at that receptor than serotonin.

An alpha-7 nicotinic acetylcholine receptor agonist disclosed herein canbe a pan-agonist or a selective agonist. An alpha-7 nicotinicacetylcholine receptor pan-agonist binds to and elicits a biologicalresponse from any alpha-7 nicotinic acetylcholine receptor irrespectiveof subunit composition. An alpha-7 nicotinic acetylcholine receptorselective agonist binds selective to a specific type of alpha-7nicotinic acetylcholine receptor, eliciting a biological response of viathese specific alpha-7 nicotinic acetylcholine receptors. For example, a5-HT₃ selective agonist can bind to and elicit a biological responsefrom only α7 nAChR homopentameric receptors or only α7 nAChRheteropentameric receptors.

An alpha-7 nicotinic acetylcholine receptor agonist disclosed hereinincludes, without limitation,(+)-N-(1-azabicyclo[2.2.2]oct-3-yl)benzo[b]furan-2-carboxamide,A-582941, Acetylcholine, Amyloid beta, Anabasine, AR-R17779,Bradanicline, Choline, Encenicline, Epiboxidine, GTS-21, ICH-3,Nicotine, PHA-543,613, PHA-709829, PNU-282,987, SSR-180,711, TC-1698,Tilorone, Tropisetron, and WAY-317,538.

The present specification discloses, in part, an activator of an alpha-7nicotinic acetylcholine receptor activity having 5-HT₃ receptorinhibitory activity. An activator of an alpha-7 nicotinic acetylcholinereceptor activity having 5-HT₃ receptor inhibitory activity is analpha-7 nicotinic acetylcholine receptor agonist disclosed herein thatalso binds to a 5-HT₃ receptor and dampens, inhibits or otherwiseprevents a biological response mediated by the 5-HT₃ receptor. Thus, anactivator of an alpha-7 nicotinic acetylcholine receptor activity having5-HT₃ receptor inhibitory activity has affinity but no efficacy for itscognate 5-HT₃ receptor. Once bound, however, an activator of an alpha-7nicotinic acetylcholine receptor activity having 5-HT₃ receptorinhibitory activity inhibit the function of agonists, inverse agonists,and partial agonists. An activator of an alpha-7 nicotinic acetylcholinereceptor activity having 5-HT₃ receptor inhibitory activity disclosedherein can mediate its effects by binding to an active orthosteric siteor by binding to an allosteric site on a 5-HT₃ receptor, or an activatorof an alpha-7 nicotinic acetylcholine receptor activity having 5-HT₃receptor inhibitory activity disclosed herein may interact at uniquebinding sites not normally involved in the biological regulation of5-HT₃ receptor activity. An activator of an alpha-7 nicotinicacetylcholine receptor activity having 5-HT₃ receptor inhibitoryactivity disclosed herein may be reversible or irreversible depending onthe longevity of the antagonist-receptor complex, which, in turn,depends on the nature of antagonist-receptor binding.

An activator of an alpha-7 nicotinic acetylcholine receptor activityhaving 5-HT₃ receptor inhibitory activity disclosed herein can have fullantagonistic activity at a 5-HT₃ receptor, a partial antagonisticactivity at a 5-HT₃ receptor, or a co-agonist antagonistic activity at a5-HT₃ receptor. An activator of an alpha-7 nicotinic acetylcholinereceptor activity having 5-HT₃ full receptor antagonistic activity at a5-HT₃ receptor bind to and inhibits the maximum biological responsemediated by a given 5-HT₃ receptor. An activator of an alpha-7 nicotinicacetylcholine receptor activity having 5-HT₃ partial receptorantagonistic activity at a 5-HT₃ receptor bind to and dampens, but doesnot completely inhibit the biological response mediated by a given 5-HT₃receptor, even at maximal receptor occupancy. An activator of an alpha-7nicotinic acetylcholine receptor activity having 5-HT₃ full receptorco-antagonistic activity at a 5-HT₃ receptor works together with other5-HT₃ receptor co-antagonists to produce the desired blocking effect ofa biological response.

An activator of an alpha-7 nicotinic acetylcholine receptor activityhaving 5-HT₃ receptor antagonistic activity disclosed herein can be anactivator of an alpha-7 nicotinic acetylcholine receptor activity having5-HT₃ full receptor pan-antagonistic activity at a 5-HT₃ receptor or anactivator of an alpha-7 nicotinic acetylcholine receptor activity having5-HT₃ selective receptor pan-antagonistic activity at a 5-HT₃ receptor.An activator of an alpha-7 nicotinic acetylcholine receptor activityhaving 5-HT₃ pan-receptor antagonistic activity binds to and dampens,inhibits, or otherwise prevents a biological response mediated by any5-HT-3 receptor irrespective of subunit composition. An activator of analpha-7 nicotinic acetylcholine receptor activity having 5-HT₃ selectivereceptor antagonistic activity binds selective to a specific type of5-HT₃ receptor and dampening, inhibiting or otherwise preventing abiological response via these specific 5-HT₃ receptors. For example, anactivator of an alpha-7 nicotinic acetylcholine receptor activity having5-HT₃ selective receptor antagonistic activity can bind to and dampen,inhibit or otherwise prevent a biological response from only 5-HT₃homopentameric receptors, or only 5-HT₃ heteropentameric receptors, oronly 5-HT₃ heteropentameric receptors of certain subunit composition,such as, e.g., 5-HT₃AC heteropentameric receptors, 5-HT₃ADheteropentameric receptors, or 5-HT₃AE heteropentameric receptors.

An activator of an alpha-7 nicotinic acetylcholine receptor activityhaving 5-HT₃ receptor antagonistic activity disclosed herein includes,without limitation, an activator of an alpha-7 nicotinic acetylcholinereceptor activity having antidepressant 5-HT₃ receptor antagonisticactivity, an activator of an alpha-7 nicotinic acetylcholine receptoractivity having antiemetic 5-HT₃ receptor antagonistic activity, anactivator of an alpha-7 nicotinic acetylcholine receptor activity havingantimalarial 5-HT₃ receptor antagonistic activity, an activator of analpha-7 nicotinic acetylcholine receptor activity having antipsychotic5-HT₃ receptor antagonistic activity, and an activator of an alpha-7nicotinic acetylcholine receptor activity having gastroprokinetic 5-HT₃receptor antagonistic activity

The present specification discloses, in part, an activator of an alpha-7nicotinic acetylcholine receptor activity having 5-HT₃ receptor inverseagonistic activity. An activator of an alpha-7 nicotinic acetylcholinereceptor activity having 5-HT₃ receptor inverse agonistic activity is acompound that binds to a 5-HT₃ receptor and reduces, inhibits, orotherwise prevents the constitutive activity of the 5-HT₃ receptor. Assuch, whereas a molecule with 5-HT₃ receptor agonistic activity causes abiological response, a molecule with 5-HT₃ receptor antagonisticactivity blocks the biological response elicited by a 5-HT₃ receptoragonist, and a molecule with 5-HT₃ receptor inverse agonistic activityexerts the opposite biological response to that of a 5-HT₃ receptoragonist, not merely an absence of the biological response as seen withan antagonistic activity. An activator of an alpha-7 nicotinicacetylcholine receptor activity having 5-HT₃ receptor inverse agonisticactivity includes, without limitation, an activator of an alpha-7nicotinic acetylcholine receptor activity having 5-HT₃ receptor fullinverse agonistic activity, an activator of an alpha-7 nicotinicacetylcholine receptor activity having 5-HT₃ receptor partial inverseagonistic activity, and an activator of an alpha-7 nicotinicacetylcholine receptor activity having 5-HT₃ receptor co-inverseagonistic activity. An activator of an alpha-7 nicotinic acetylcholinereceptor activity having 5-HT₃ receptor inverse agonistic activityincludes, without limitation, an activator of an alpha-7 nicotinicacetylcholine receptor activity having 5-HT₃ receptor pan inverseagonistic activity and an activator of an alpha-7 nicotinicacetylcholine receptor activity having 5-HT₃ receptor selective inverseagonistic activity.

The present specification discloses, in part, a therapeuticallyeffective amount. With respect to a combination therapy disclosedherein, an activator of alpha-7 nicotinic acetylcholine receptoractivity having 5-HT₃ receptor inhibitory activity, a 5-HT₃ receptoragonist, an activator of an alpha-7 nicotinic acetylcholine receptoractivity having 5-HT₃ receptor antagonistic activity and an activator ofan alpha-7 nicotinic acetylcholine receptor activity having 5-HT₃receptor inverse agonistic activity, collectively called “active agent”,are each used or administered in a therapeutically effective amount. Atherapeutically effective amount of an active agent present in acombination therapy is an amount sufficient to treat a schizophrenicdisorder or pathology. In aspects of this embodiment, a therapeuticallyeffective amount of an active agent present in a combination therapy isan amount sufficient to reduce one or more physiological conditions orsymptoms associated with a schizophrenic disorder or pathology or anamount sufficient to protect the individual against one or morephysiological conditions or symptoms associated with a schizophrenicdisorder or pathology. As used herein, the term “therapeuticallyeffective amount” includes the terms “amount sufficient”,“therapeutically sufficient amount”, “effective amount”, “effectivedose”, or “therapeutically effective dose” and refers to the minimumamount of an active agent disclosed herein present in a combinationtherapy disclosed herein necessary to achieve the desired therapeuticeffect and includes an amount sufficient to reduce or inhibit one ormore physiological conditions or symptoms associated with aschizophrenic disorder or pathology.

In aspects of this embodiment, a therapeutically effective amount of anactive agent disclosed herein present in a combination therapy disclosedherein reduces or inhibits one or more physiological conditions orsymptoms associated with a schizophrenic disorder or pathology by, e.g.,at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, atleast 60%, at least 70%, at least 80%, at least 90% or at least 100%. Inother aspects of this embodiment, an effective amount of an active agentdisclosed herein present in a combination therapy disclosed hereinreduces or inhibits one or more physiological conditions or symptomsassociated with a schizophrenic disorder or pathology by, e.g., at most10%, at most 20%, at most 30%, at most 40%, at most 50%, at most 60%, atmost 70%, at most 80%, at most 90% or at most 100%. In yet other aspectsof this embodiment, an effective amount of an active agent disclosedherein present in a combination therapy disclosed herein reduces orinhibits one or more physiological conditions or symptoms associatedwith a schizophrenic disorder or pathology by, e.g., about 10% to about100%, about 10% to about 90%, about 10% to about 80%, about 10% to about70%, about 10% to about 60%, about 10% to about 50%, about 10% to about40%, about 20% to about 100%, about 20% to about 90%, about 20% to about80%, about 20% to about 20%, about 20% to about 60%, about 20% to about50%, about 20% to about 40%, about 30% to about 100%, about 30% to about90%, about 30% to about 80%, about 30% to about 70%, about 30% to about60%, or about 30% to about 50%. In still other aspects of thisembodiment, an effective amount of an active agent disclosed hereinpresent in a combination therapy disclosed herein reduces or inhibitsone or more physiological conditions or symptoms associated with aschizophrenic disorder or pathology for, e.g., at least one week, atleast one month, at least two months, at least three months, at leastfour months, at least five months, at least six months, at least sevenmonths, at least eight months, at least nine months, at least tenmonths, at least eleven months, or at least twelve months.

In some embodiments, a therapeutic effective amount a therapeuticeffective amount of a combined therapy comprising about 0.1 mg to about1,000 mg of an alpha-7 nicotinic acetylcholine receptor activity having5-HT₃ receptor inhibitory activity and about 0.1 mg to about 1,000 mg ofa 5-HT₃ receptor agonist. In aspects of these embodiments, a therapeuticeffective amount a therapeutic effective amount of a combined therapycomprising about 0.25 mg to about 750 mg, about 0.5 mg to about 500 mg,about 0.75 mg to about 250 mg, or about 1 mg to about 250 mg, of analpha-7 nicotinic acetylcholine receptor activity having 5-HT₃ receptorinhibitory activity and about 0.25 mg to about 750 mg, about 0.5 mg toabout 500 mg, about 0.75 mg to about 250 mg, or about 1 mg to about 250mg, of a 5-HT₃ receptor agonist.

In some embodiments, a therapeutic effective amount of a combinedtherapy comprising about 0.1 mg to about 1,000 mg of an activator of analpha-7 nicotinic acetylcholine receptor activity having 5-HT₃ receptorantagonistic activity and about 0.1 mg to about 1,000 mg of a 5-HT₃receptor agonist. In aspects of these embodiments, a therapeuticeffective amount of a combined therapy comprising about 0.25 mg to about750 mg, about 0.5 mg to about 500 mg, about 0.75 mg to about 250 mg, orabout 1 mg to about 250 mg, of an activator of an alpha-7 nicotinicacetylcholine receptor activity having 5-HT₃ receptor antagonisticactivity and about 0.25 mg to about 750 mg, about 0.5 mg to about 500mg, about 0.75 mg to about 250 mg, or about 1 mg to about 250 mg, of a5-HT₃ receptor agonist.

In some embodiments, a therapeutic effective amount of a combinedtherapy comprising about 0.1 mg to about 1,000 mg of an activator of analpha-7 nicotinic acetylcholine receptor activity having 5-HT₃ receptorinverse agonistic activity and about 0.1 mg to about 1,000 mg of a 5-HT₃receptor agonist. In aspects of these embodiments, a therapeuticeffective amount of a combined therapy comprising about 0.25 mg to about750 mg, about 0.5 mg to about 500 mg, about 0.75 mg to about 250 mg, orabout 1 mg to about 250 mg, of an activator of an alpha-7 nicotinicacetylcholine receptor activity having 5-HT₃ receptor inverse agonisticactivity and about 0.25 mg to about 750 mg, about 0.5 mg to about 500mg, about 0.75 mg to about 250 mg, or about 1 mg to about 250 mg, of a5-HT₃ receptor agonist.

In some embodiments, a therapeutic effective amount of a combinedtherapy comprising about 1 mg to about 100 mg of a Tropisetron and about0.1 mg to about 5 mg of a Varenicline. In some embodiments, atherapeutic effective amount of a combined therapy comprising about 2 mgto about 75 mg of a Tropisetron and about 0.25 mg to about 4 mg of aVarenicline. In some embodiments, a therapeutic effective amount of acombined therapy comprising about 5 mg to about 50 mg of a Tropisetronand about 0.5 mg to about 2 mg of a Varenicline.

In some embodiments, a therapeutic effective amount of a combinedtherapy can be one where one, some or all of the active agents are in anoptimal therapeutic amount. An optimal therapeutic amount is a quantityof an active agent that will most effectively produce the desiredtherapeutic effect while remaining in the range of acceptable toxicity.

In some embodiments, a therapeutic effective amount of a combinedtherapy can be one where one, some or all of the active agents are in asuboptimal therapeutic amount. A suboptimal therapeutic amount aquantity of an active agent that is below the optimal therapeutic amountfor that active agent but still provides some degree of a therapeuticeffect desired. In aspects of these embodiments, a suboptimaltherapeutic amount of an active agent is, e.g., less than 80%, less than75%, less than 70%, less than 60%, less than 55%, less than 50%, of theoptimal therapeutic amount for that active agent. In aspects of theseembodiments, a suboptimal therapeutic amount of an active agent is,e.g., about 10% to about 80%, about 20% to about 80%, about 30% to about80%, about 40% to about 80%, or about 50% to about 80%, of the optimaltherapeutic amount for that active agent.

In some embodiments, a therapeutic effective amount of a combinedtherapy can be one where one, some or all of the active agents are in anon-therapeutic amount. A non-therapeutic amount a quantity of an activeagent that is a suboptimal therapeutic amount for that active agent butprovides therapeutic effect. In aspects of these embodiments, anon-therapeutic amount of an active agent is, e.g., less than 80%, lessthan 75%, less than 70%, less than 60%, less than 55%, less than 50%, ofthe suboptimal therapeutic amount for that active agent. In aspects ofthese embodiments, a non-therapeutic amount of an active agent is, e.g.,about 10% to about 80%, about 20% to about 80%, about 30% to about 80%,about 40% to about 80%, or about 50% to about 80%, of the suboptimaltherapeutic amount for that active agent.

In some embodiments, a therapeutic effective amount of a combinedtherapy comprising an alpha-7 nicotinic acetylcholine receptor activityhaving 5-HT₃ receptor inhibitory activity and a 5-HT₃ receptor agonistis one where 1) the amount of an activator of an alpha-7 nicotinicacetylcholine receptor activity having 5-HT₃ receptor inhibitoryactivity is a suboptimal therapeutic amount when administered alone, 2)the amount of a 5-HT₃ receptor agonist is a suboptimal therapeuticamount when administered alone, or 3) the amount of an activator of analpha-7 nicotinic acetylcholine receptor activity having 5-HT₃ receptorinhibitory activity and the amount of a 5-HT₃ receptor agonist are bothsuboptimal therapeutic amount when each is administered alone. Inaspects of these embodiments, a therapeutic effective amount of acombined therapy comprising an alpha-7 nicotinic acetylcholine receptoractivity having 5-HT₃ receptor inhibitory activity and a 5-HT₃ receptoragonist is one where 1) the amount of an activator of an alpha-7nicotinic acetylcholine receptor activity having 5-HT₃ receptorinhibitory activity is a non-therapeutic amount when administered alone,2) the amount of a 5-HT₃ receptor agonist is a non-therapeutic amountwhen administered alone, or 3) the amount of an activator of an alpha-7nicotinic acetylcholine receptor activity having 5-HT₃ receptorinhibitory activity and the amount of a 5-HT₃ receptor agonist are bothnon-therapeutic amount when each is administered alone.

In some embodiments, a therapeutic effective amount of a combinedtherapy comprising an activator of an alpha-7 nicotinic acetylcholinereceptor activity having 5-HT₃ receptor antagonistic activity and a5-HT₃ receptor agonist is one where 1) the amount of an activator of analpha-7 nicotinic acetylcholine receptor activity having 5-HT₃ receptorantagonistic activity is a suboptimal therapeutic amount whenadministered alone, 2) the amount of a 5-HT₃ receptor agonist is asuboptimal therapeutic amount when administered alone, or 3) the amountof an activator of an alpha-7 nicotinic acetylcholine receptor activityhaving 5-HT₃ receptor antagonistic activity and the amount of a 5-HT₃receptor agonist are both suboptimal therapeutic amount when each isadministered alone. In aspects of these embodiments, a therapeuticeffective amount of a combined therapy comprising an activator of analpha-7 nicotinic acetylcholine receptor activity having 5-HT₃ receptorantagonistic activity and a 5-HT₃ receptor agonist is one where 1) theamount of an activator of an alpha-7 nicotinic acetylcholine receptoractivity having 5-HT₃ receptor antagonistic activity is anon-therapeutic amount when administered alone, 2) the amount of a 5-HT₃receptor agonist is a non-therapeutic amount when administered alone, or3) the amount of an activator of an alpha-7 nicotinic acetylcholinereceptor activity having 5-HT₃ receptor antagonistic activity and theamount of a 5-HT₃ receptor agonist are both non-therapeutic amounts wheneach is administered alone.

In some embodiments, a therapeutic effective amount of a combinedtherapy comprising an alpha-7 nicotinic acetylcholine receptor agonisthaving 5-HT₃ receptor antagonistic activity and a 5-HT₃ receptor agonistis one where 1) the amount of an alpha-7 nicotinic acetylcholinereceptor agonist having 5-HT₃ receptor antagonistic activity is asuboptimal therapeutic amount when administered alone, 2) the amount ofa 5-HT₃ receptor agonist is a suboptimal therapeutic amount whenadministered alone, or 3) the amount of an alpha-7 nicotinicacetylcholine receptor agonist having 5-HT₃ receptor antagonisticactivity and the amount of a 5-HT₃ receptor agonist are both suboptimaltherapeutic amount when each is administered alone. In aspects of theseembodiments, a therapeutic effective amount of a combined therapycomprising an alpha-7 nicotinic acetylcholine receptor agonist having5-HT₃ receptor antagonistic activity and a 5-HT₃ receptor agonist is onewhere 1) the amount of an alpha-7 nicotinic acetylcholine receptoragonist having 5-HT₃ receptor antagonistic activity is a non-therapeuticamount when administered alone, 2) the amount of a 5-HT₃ receptoragonist is a non-therapeutic amount when administered alone, or 3) theamount of an alpha-7 nicotinic acetylcholine receptor agonist having5-HT₃ receptor antagonistic activity and the amount of a 5-HT₃ receptoragonist are both non-therapeutic amounts when each is administeredalone.

In some embodiments, a therapeutic effective amount of a combinedtherapy comprising an activator of an alpha-7 nicotinic acetylcholinereceptor activity having 5-HT₃ receptor inverse agonistic activity and a5-HT₃ receptor agonist is one where 1) the amount of an activator of analpha-7 nicotinic acetylcholine receptor activity having 5-HT₃ receptorinverse agonistic activity is a suboptimal therapeutic amount whenadministered alone, 2) the amount of a 5-HT₃ receptor agonist is asuboptimal therapeutic amount when administered alone, or 3) the amountof an activator of an alpha-7 nicotinic acetylcholine receptor activityhaving 5-HT₃ receptor inverse agonistic activity and the amount of a5-HT₃ receptor agonist are both suboptimal therapeutic amount when eachis administered alone. In aspects of these embodiments, a therapeuticeffective amount of a combined therapy comprising an activator of analpha-7 nicotinic acetylcholine receptor activity having 5-HT₃ receptorinverse agonistic activity and a 5-HT₃ receptor agonist is one where 1)the amount of an activator of an alpha-7 nicotinic acetylcholinereceptor activity having 5-HT₃ receptor inverse agonistic activity is anon-therapeutic amount when administered alone, 2) the amount of a 5-HT₃receptor agonist is a non-therapeutic amount when administered alone, or3) the amount of an activator of an alpha-7 nicotinic acetylcholinereceptor activity having 5-HT₃ receptor inverse agonistic activity andthe amount of a 5-HT₃ receptor agonist are both non-therapeutic amountswhen each is administered alone.

In some embodiments, a therapeutic effective amount of a combinedtherapy comprising an alpha-7 nicotinic acetylcholine receptor agonisthaving 5-HT₃ receptor inverse agonistic activity and a 5-HT₃ receptoragonist is one where 1) the amount of an alpha-7 nicotinic acetylcholinereceptor agonist having 5-HT₃ receptor inverse agonistic activity is asuboptimal therapeutic amount when administered alone, 2) the amount ofa 5-HT₃ receptor agonist is a suboptimal therapeutic amount whenadministered alone, or 3) the amount of an alpha-7 nicotinicacetylcholine receptor agonist having 5-HT₃ receptor inverse agonisticactivity and the amount of a 5-HT₃ receptor agonist are both suboptimaltherapeutic amount when each is administered alone. In aspects of theseembodiments, a therapeutic effective amount of a combined therapycomprising an alpha-7 nicotinic acetylcholine receptor agonist having5-HT₃ receptor inverse agonistic activity and a 5-HT₃ receptor agonistis one where 1) the amount of an alpha-7 nicotinic acetylcholinereceptor agonist having 5-HT₃ receptor inverse agonistic activity is anon-therapeutic amount when administered alone, 2) the amount of a 5-HT₃receptor agonist is a non-therapeutic amount when administered alone, or3) the amount of an alpha-7 nicotinic acetylcholine receptor agonisthaving 5-HT₃ receptor inverse agonistic activity and the amount of a5-HT₃ receptor agonist are both non-therapeutic amounts when each isadministered alone.

In some embodiments, a therapeutic effective amount of a combinedtherapy comprising a Tropisetron and a Varenicline is one where 1) theamount of a Tropisetron is a suboptimal therapeutic amount whenadministered alone, 2) the amount of a Varenicline is a suboptimaltherapeutic amount when administered alone, or 3) the amount of aTropisetron and the amount of a Varenicline are both suboptimaltherapeutic amounts when each is administered alone. In aspects of theseembodiments, a therapeutic effective amount of a combined therapycomprising a Tropisetron and a Varenicline is one where 1) the amount ofa Tropisetron is a non-therapeutic amount when administered alone, 2)the amount of a Varenicline is a non-therapeutic amount whenadministered alone, or 3) the amount of a Tropisetron and the amount ofa Varenicline are both non-therapeutic amounts when each is administeredalone.

The actual therapeutic effective amount of an active agent disclosedherein present in a combination therapy disclosed herein to be used oradministered to an individual can be determined by a person of ordinaryskill in the art by taking into account factors, including, withoutlimitation, the type of schizophrenic disorder or pathology, theparticular physiological conditions or symptoms associated with theschizophrenic disorder or pathology, the cause of the schizophrenicdisorder or pathology, the severity of the schizophrenic disorder orpathology, the degree of relief desired for schizophrenic disorder orpathology, the duration of relief desired for schizophrenic disorder orpathology, the particular active agent used in a combination therapy,the rate of excretion of the particular active agent used in acombination therapy, the pharmacodynamics of the particular active agentused present in a combination therapy, the nature of the other compoundsto be included in the combination therapy, the particular route ofadministration used, the particular characteristics, history and riskfactors of the individual, such as, e.g., age, weight, general healthand the like, or any combination thereof. Additionally, where repeatedadministration of a combination therapy disclosed herein is used, theactual therapeutically effective amount will further depend uponfactors, including, without limitation, the frequency of administration,the half-life of an active agent disclosed herein present in acombination therapy, or any combination thereof. It is known by a personof ordinary skill in the art that an effective amount of an active agentdisclosed herein present in a combination therapy can be extrapolatedfrom in vitro assays and in vivo administration studies using animalmodels prior to administration to humans. Wide variations in thenecessary effective amount are to be expected in view of the differingefficiencies of the various routes of administration. For instance, oraluse or administration generally would be expected to require higherdosage levels than use or administration by intravenous or intravitrealinjection. Variations in these dosage levels can be adjusted usingstandard empirical routines of optimization, which are well-known to aperson of ordinary skill in the art. The precise therapeuticallyeffective dosage levels and patterns are preferably determined by theattending healthcare professional in consideration of theabove-identified factors.

Dosing can be single dosage or cumulative (serial dosing), and can bereadily determined by one skilled in the art. For instance, treatment ofa schizophrenic disorder or pathology may comprise a one-timeadministration of a combination therapy disclosed herein. As anon-limiting example, a combination therapy can be administered once toan individual, e.g., as a single injection or deposition. Alternatively,treatment of a schizophrenic disorder or pathology may comprise multipleadministrations of a combination therapy disclosed herein carried outover a range of time periods, such as, e.g., daily, once every few days,weekly, monthly, or yearly. As a non-limiting example, a combinationtherapy can be administered one, two, three, four, five or six timesyearly to an individual. The timing of administration can vary fromindividual to individual, depending upon such factors as the severity ofan individual's symptoms. For example, a combination therapy can beadministered to an individual once every three months for an indefiniteperiod of time, or until the individual no longer requires therapy. Aperson of ordinary skill in the art will recognize that the condition ofthe individual can be monitored throughout the course of treatment andthat use or administration of a combination therapy disclosed herein canbe adjusted accordingly.

The present specification discloses, in part, a schizophrenic disorder.A schizophrenic disorder is a group of psychiatric disorderscharacterized by the deterioration in the functional interaction betweenthought, emotion, and behavior leading to a wide array of disturbancesin cognition, perception, and mood. Characteristically, an individualwith a schizophrenic disorder exhibits a gross distortion of reality,significant disturbances of language and cognitive function, extensivewithdrawal from social interaction, disorganization, and fragmentationof thought, altered perception, and inappropriate emotional reaction.

The clinical features of a schizophrenic disorder can be clustered intothree symptom groups, positive symptoms, negative symptom, and cognitivesymptoms. Positive symptoms are classified as fixed, false feelings orbehaviors involving real-life situations that could be true but aresimply manifestations of psychosis, such as, e.g., delusions,hallucinations, paranoia, thought disorders (disorganized thinking,speech or behavior, neologism) and movement disorders (clumsy,uncoordinated, repetitious movements, catatonia). Negative symptoms areclassified as deficits or reductions in normal emotion and behavior,such as, e.g., affective disturbances (immobile expression, monotonousvoice), reduced interest or lack of pleasure in everyday activities(anhedonia, like depression), lack of motivation (avolition), decreasedability to initiate and sustain planned activity, poverty of speech(alogia), infrequent speech (even when forced to interact), and socialwithdrawal. Cognitive symptoms are classified as deficits in the mentalprocesses of comprehension, judgement, memory, and reasoning, such as,e.g., problems in selective attention, working memory, executivefunction, episodic memory, language comprehension and social-emotionalprocessing.

Non-limiting examples of a schizophrenic disorder include schizophrenia,a schizophreniform disorder, schizoaffective disorder, and a schizotypalpersonality disorder. A schizophrenia is one where an individual hassymptoms of schizophrenia that last for six months or more. Aschizoaffective disorder is one where an individual has symptoms of bothschizophrenia and a mood disorder, such as depression or bipolardisorder. A schizophreniform disorder is one where an individual hassymptoms of schizophrenia, but the symptoms last for less than sixmonths. A schizotypal personality disorder is a schizophrenia-likecondition characterized by defects in interpersonal relationships anddisturbed thought patterns, appearance, behavior that are not severeenough to meet the clinical criteria of schizophrenia.

A schizophrenia can be divided into five subtypes based on the type andfrequency of positive and negative symptoms, namely disorganized,catatonic, paranoid, undifferentiated and residual. Disorganized(hebephrenic) schizophrenia is characterized by individuals havingdisorganized, incoherent thinking; shallow, flat, inappropriate, and/orsilly emotional responses to a situation (affect); and regressivebehavior without systematized delusions. Catatonic schizophrenia ischaracterized by individuals having psychomotor disturbance which mayinvolve stupor, rigidity, excitement, negativism, or bizarre posturing,or an alteration among these behaviors; associated features includemutism, stereotypy, and waxy flexibility. Paranoid schizophrenia ischaracterized by individuals having persecutory or grandiose delusions,delusional jealousy, or hallucinations with persecutory or grandiosecontent. Undifferentiated schizophrenia is characterized by individualshaving positive and negative symptoms of schizophrenia but which do notmeet the specific criteria for the paranoid, disorganized, or catatonicsubtypes. Residual schizophrenia is characterized by individuals havinga previous schizophrenic episode but do not currently present with anypositive symptoms, although negative symptoms may persist.

In addition to these five symptomatic subtypes, individuals can also beclassified based on other criteria including susceptibility, initialevent, duration, antipsychotic drug resistance and cognitive symptoms.For example, an individual who begins experiencing some psychoticsymptoms, but these symptoms can also occur in people who will neverdevelop a schizophrenic disorder is classified as being at ultra-highrisk (UHR) or at-risk mental state (ARMS) for psychosis. An individualwho experiences psychotic symptoms or an episode of schizophrenicdisorder for the first time is classified as having first-episodepsychosis (FEP). An individual suffering from a schizophrenic disorderwhose positive and negative symptoms are being successfully beingmanaged with a therapy comprising an antipsychotic medication isclassified as having a chronic treatment responsive schizophrenia. Anindividual suffering from a schizophrenic disorder who after an initialperiod of therapeutic success becomes resistant to an antipsychoticmedication is classified as having a treatment-resistant schizophrenia(TRS). An individual suffering from a schizophrenic disorder whosepositive and negative symptoms are being successfully being managed witha therapy comprising an antipsychotic medication but is still afflictedwith cognitive symptoms is classified as having a cognitive impairmentassociated with schizophrenia (CIAS).

In one embodiment, a method of treating a schizophrenic disordercomprises, consists essentially of, or consists of administering acombined therapy comprising, consisting essentially of, or consisting ofone or more activators of an alpha-7 nicotinic acetylcholine receptoractivity having 5-HT₃ receptor inhibitory activity and one or moreactivators of 5-HT₃ receptor activity. In aspects of this embodiment, amethod of treating a schizophrenia comprises, consists essentially of,or consists of administering a combined therapy comprising, consistingessentially of, or consisting of one or more activators of an alpha-7nicotinic acetylcholine receptor activity having 5-HT₃ receptorinhibitory activity and one or more activators of 5-HT₃ receptoractivity. In other aspects of this embodiment, a method of treating atreatment-resistant schizophrenia comprises, consists essentially of, orconsists of administering a combined therapy comprising, consistingessentially of, or consisting of one or more activators of an alpha-7nicotinic acetylcholine receptor activity having 5-HT₃ receptorinhibitory activity and one or more activators of 5-HT₃ receptoractivity. In yet other aspects of this embodiment, a method of treatinga cognitive impaired schizophrenia comprises, consists essentially of,or consists of administering a combined therapy comprising, consistingessentially of, or consisting of one or more activators of an alpha-7nicotinic acetylcholine receptor activity having 5-HT₃ receptorinhibitory activity and one or more activators of 5-HT₃ receptoractivity.

In one embodiment, a method of treating a schizophrenic disordercomprises, consists essentially of, or consists of administering acombined therapy comprising, consisting essentially of, or consisting ofa therapeutically effective amount of one or more activators of analpha-7 nicotinic acetylcholine receptor activity having 5-HT₃ receptorinhibitory activity and a therapeutically effective amount of one ormore activators of 5-HT₃ receptor activity. In aspects of thisembodiment, a method of treating a schizophrenia comprises, consistsessentially of, or consists of administering a combined therapycomprising, consisting essentially of, or consisting of atherapeutically effective amount of one or more activators of an alpha-7nicotinic acetylcholine receptor activity having 5-HT₃ receptorinhibitory activity and a therapeutically effective amount of one ormore activators of 5-HT₃ receptor activity. In other aspects of thisembodiment, a method of treating a treatment-resistant schizophreniacomprises, consists essentially of, or consists of administering acombined therapy comprising, consisting essentially of, or consisting ofa therapeutically effective amount of one or more activators of analpha-7 nicotinic acetylcholine receptor activity having 5-HT₃ receptorinhibitory activity and a therapeutically effective amount of one ormore activators of 5-HT₃ receptor activity. In yet other aspects of thisembodiment, a method of treating a cognitive impaired schizophreniacomprises, consists essentially of, or consists of administering acombined therapy comprising, consisting essentially of, or consisting ofa therapeutically effective amount of one or more activators of analpha-7 nicotinic acetylcholine receptor activity having 5-HT₃ receptorinhibitory activity and a therapeutically effective amount of one ormore activators of 5-HT₃ receptor activity. In some embodiments, atherapeutic effective amount of one or more activators of an alpha-7nicotinic acetylcholine receptor activity having 5-HT₃ receptorinhibitory activity is an amount that is a suboptimal therapeutic amountwhen administer alone. In some embodiments, a therapeutic effectiveamount of one or more activators of an alpha-7 nicotinic acetylcholinereceptor activity having 5-HT₃ receptor inhibitory activity is an amountthat is a non-therapeutic amount when administer alone. In someembodiments, a therapeutic effective amount of one or more 5-HT₃receptor agonists is an amount that is a suboptimal therapeutic amount.In some embodiments, a therapeutic effective amount of one or more 5-HT₃receptor agonists is an amount that is a non-therapeutic amount whenadminister alone. In some embodiments, a therapeutic effective amount ofone or more activators of an alpha-7 nicotinic acetylcholine receptoractivity having 5-HT₃ receptor inhibitory activity is an amount that isa suboptimal therapeutic amount when administer alone and a therapeuticeffective amount of one or more 5-HT₃ receptor agonists is an amountthat is a suboptimal therapeutic amount when administer alone. In someembodiments, a therapeutic effective amount of one or more activators ofan alpha-7 nicotinic acetylcholine receptor activity having 5-HT₃receptor inhibitory activity is an amount that is a non-therapeuticamount when administer alone and a therapeutic effective amount of oneor more 5-HT₃ receptor agonists is an amount that is a non-therapeuticamount when administer alone.

In one embodiment, a method of treating a schizophrenic disordercomprises, consists essentially of, or consists of administering acombined therapy comprising, consisting essentially of, or consisting ofone or more alpha-7 nicotinic acetylcholine receptor agonists having5-HT₃ receptor antagonistic activity and one or more 5-HT₃ receptoragonists. In aspects of this embodiment, a method of treating aschizophrenia comprises, consists essentially of, or consists ofadministering a combined therapy comprising, consisting essentially of,or consisting of one or more alpha-7 nicotinic acetylcholine receptoragonists having 5-HT₃ receptor antagonistic activity and one or more5-HT₃ receptor agonists. In other aspects of this embodiment, a methodof treating a treatment-resistant schizophrenia comprises, consistsessentially of, or consists of administering a combined therapycomprising, consisting essentially of, or consisting of one or morealpha-7 nicotinic acetylcholine receptor agonists having 5-HT₃ receptorantagonistic activity and one or more 5-HT₃ receptor agonists. In yetother aspects of this embodiment, a method of treating a cognitiveimpaired schizophrenia comprises, consists essentially of, or consistsof administering a combined therapy comprising, consisting essentiallyof, or consisting of one or more alpha-7 nicotinic acetylcholinereceptor agonists having 5-HT₃ receptor antagonistic activity and one ormore 5-HT₃ receptor agonists.

In one embodiment, a method of treating a schizophrenic disordercomprises, consists essentially of, or consists of administering acombined therapy comprising, consisting essentially of, or consisting ofa therapeutically effective amount of one or more alpha-7 nicotinicacetylcholine receptor agonists having 5-HT₃ receptor antagonisticactivity and a therapeutically effective amount of one or more 5-HT₃receptor agonists. In aspects of this embodiment, a method of treating aschizophrenia comprises, consists essentially of, or consists ofadministering a combined therapy comprising, consisting essentially of,or consisting of a therapeutically effective amount of one or morealpha-7 nicotinic acetylcholine receptor agonists having 5-HT₃ receptorantagonistic activity and a therapeutically effective amount of one ormore 5-HT₃ receptor agonists. In other aspects of this embodiment, amethod of treating a treatment-resistant schizophrenia comprises,consists essentially of, or consists of administering a combined therapycomprising, consisting essentially of, or consisting of atherapeutically effective amount of one or more alpha-7 nicotinicacetylcholine receptor agonists having 5-HT₃ receptor antagonisticactivity and a therapeutically effective amount of one or more 5-HT₃receptor agonists. In yet other aspects of this embodiment, a method oftreating a cognitive impaired schizophrenia comprises, consistsessentially of, or consists of administering a combined therapycomprising, consisting essentially of, or consisting of atherapeutically effective amount of one or more alpha-7 nicotinicacetylcholine receptor agonists having 5-HT₃ receptor antagonisticactivity and a therapeutically effective amount of one or more 5-HT₃receptor agonists. In some embodiments, a therapeutic effective amountof one or more alpha-7 nicotinic acetylcholine receptor agonists having5-HT₃ receptor antagonistic activity is an amount that is a suboptimaltherapeutic amount when administer alone. In some embodiments, atherapeutic effective amount of one or more alpha-7 nicotinicacetylcholine receptor agonists having 5-HT₃ receptor antagonisticactivity is an amount that is a non-therapeutic amount when administeralone. In some embodiments, a therapeutic effective amount of one ormore 5-HT₃ receptor agonists is an amount that is a suboptimaltherapeutic amount when administer alone. In some embodiments, atherapeutic effective amount of one or more 5-HT₃ receptor agonists isan amount that is a non-therapeutic amount when administer alone. Insome embodiments, a therapeutic effective amount of one or more alpha-7nicotinic acetylcholine receptor agonists having 5-HT₃ receptorantagonistic activity is an amount that is a suboptimal therapeuticamount when administer alone and a therapeutic effective amount of oneor more 5-HT₃ receptor agonists is an amount that is a suboptimaltherapeutic amount when administer alone. In some embodiments, atherapeutic effective amount of one or more alpha-7 nicotinicacetylcholine receptor agonists having 5-HT₃ receptor antagonisticactivity is an amount that is a non-therapeutic amount when administeralone and a therapeutic effective amount of one or more 5-HT₃ receptoragonists is an amount that is a non-therapeutic amount when administeralone.

In one embodiment, a method of treating a schizophrenic disordercomprises, consists essentially of, or consists of administering acombined therapy comprising, consisting essentially of, or consisting ofone or more alpha-7 nicotinic acetylcholine receptor agonists having5-HT₃ receptor inverse agonistic activity and one or more 5-HT₃ receptoragonists. In aspects of this embodiment, a method of treating aschizophrenia comprises, consists essentially of, or consists ofadministering a combined therapy comprising, consisting essentially of,or consisting of one or more alpha-7 nicotinic acetylcholine receptoragonists having 5-HT₃ receptor inverse agonistic activity and one ormore 5-HT₃ receptor agonists. In other aspects of this embodiment, amethod of treating a treatment-resistant schizophrenia comprises,consists essentially of, or consists of administering a combined therapycomprising, consisting essentially of, or consisting of one or morealpha-7 nicotinic acetylcholine receptor agonists having 5-HT₃ receptorinverse agonistic activity and one or more 5-HT₃ receptor agonists. Inyet other aspects of this embodiment, a method of treating a cognitiveimpaired schizophrenia comprises, consists essentially of, or consistsof administering a combined therapy comprising, consisting essentiallyof, or consisting alpha-7 nicotinic acetylcholine receptor agonistshaving 5-HT₃ receptor inverse agonistic activity and one or more 5-HT₃receptor agonists.

In one embodiment, a method of treating a schizophrenic disordercomprises, consists essentially of, or consists of administering acombined therapy comprising, consisting essentially of, or consisting ofa therapeutically effective amount of one or more alpha-7 nicotinicacetylcholine receptor agonists having 5-HT₃ receptor inverse agonisticactivity and a therapeutically effective amount of one or more 5-HT₃receptor agonists. In aspects of this embodiment, a method of treating aschizophrenia comprises, consists essentially of, or consists ofadministering a combined therapy comprising, consisting essentially of,or consisting of a therapeutically effective amount alpha-7 nicotinicacetylcholine receptor agonists having 5-HT₃ receptor inverse agonisticactivity and a therapeutically effective amount of one or more 5-HT₃receptor agonists. In other aspects of this embodiment, a method oftreating a treatment resistant schizophrenia comprises, consistsessentially of, or consists of administering a combined therapycomprising, consisting essentially of, or consisting of atherapeutically effective amount alpha-7 nicotinic acetylcholinereceptor agonists having 5-HT₃ receptor inverse agonistic activity and atherapeutically effective amount of one or more 5-HT₃ receptor agonists.In yet other aspects of this embodiment, a method of treating acognitive impaired schizophrenia comprises, consists essentially of, orconsists of administering a combined therapy comprising, consistingessentially of, or consisting of a therapeutically effective amount ofone or more alpha-7 nicotinic acetylcholine receptor agonists having5-HT₃ receptor inverse agonistic activity and a therapeuticallyeffective amount of one or more 5-HT₃ receptor agonists. In someembodiments, a therapeutic effective amount of one or more alpha-7nicotinic acetylcholine receptor agonists having 5-HT₃ receptor inverseagonistic activity is an amount that is a suboptimal therapeutic amountwhen administer alone. In some embodiments, a therapeutic effectiveamount of one or more alpha-7 nicotinic acetylcholine receptor agonistshaving 5-HT₃ receptor inverse agonistic activity is an amount that is anon-therapeutic amount when administer alone. In some embodiments, atherapeutic effective amount of one or more 5-HT₃ receptor agonists isan amount that is a suboptimal therapeutic amount when administer alone.In some embodiments, a therapeutic effective amount of one or more 5-HT₃receptor agonists is an amount that is a non-therapeutic amount whenadminister alone. In some embodiments, a therapeutic effective amount ofone or more alpha-7 nicotinic acetylcholine receptor agonists having5-HT₃ receptor inverse agonistic activity is an amount that is asuboptimal therapeutic amount when administer alone and a therapeuticeffective amount of one or more 5-HT₃ receptor agonists is an amountthat is a suboptimal therapeutic amount when administer alone. In someembodiments, a therapeutic effective amount of one or more alpha-7nicotinic acetylcholine receptor agonists having 5-HT₃ receptor inverseagonistic activity is an amount that is a non-therapeutic amount whenadminister alone and a therapeutic effective amount of one or more 5-HT₃receptor agonists is an amount that is a non-therapeutic amount whenadminister alone.

In a preferred embodiment, a method of treating a schizophrenic disordercomprises, consists essentially of, or consists of administering acombined therapy comprising, consisting essentially of, or consisting ofVarenicline and Tropisetron. In aspects of this embodiment, a method oftreating a schizophrenia comprises, consists essentially of, or consistsof administering a combined therapy comprising, consisting essentiallyof, or consisting of Varenicline and Tropisetron. In other aspects ofthis embodiment, a method of treating a treatment resistantschizophrenia comprises, consists essentially of, or consists ofadministering a combined therapy comprising, consisting essentially of,or consisting of Varenicline and Tropisetron. In yet other aspects ofthis embodiment, a method of treating a cognitive impaired schizophreniacomprises, consists essentially of, or consists of administering acombined therapy comprising, consisting essentially of, or consisting ofVarenicline and Tropisetron.

In a more preferred embodiment, a method of treating a schizophrenicdisorder comprises, consists essentially of, or consists ofadministering a combined therapy comprising, consisting essentially of,or consisting of a therapeutically effective amount of Varenicline and atherapeutically effective amount of Tropisetron. In aspects of thisembodiment, a method of treating a schizophrenia comprises, consistsessentially of, or consists of administering a combined therapycomprising, consisting essentially of, or consisting of atherapeutically effective amount of Varenicline and a therapeuticallyeffective amount of Tropisetron. In other aspects of this embodiment, amethod of treating a treatment resistant schizophrenia comprises,consists essentially of, or consists of administering a combined therapycomprising, consisting essentially of, or consisting of atherapeutically effective amount of Varenicline and a therapeuticallyeffective amount of Tropisetron. In yet other aspects of thisembodiment, a method of treating a cognitive impaired schizophreniacomprises, consists essentially of, or consists of administering acombined therapy comprising, consisting essentially of, or consisting ofa therapeutically effective amount of Varenicline and a therapeuticallyeffective amount of Tropisetron. In some embodiments, a therapeuticeffective amount of a Tropisetron is an amount that is a suboptimaltherapeutic amount when administer alone. In some embodiments, atherapeutic effective amount of a Tropisetron is an amount that is anon-therapeutic amount when administer alone. In some embodiments, atherapeutic effective amount of a Varenicline is an amount that is asuboptimal therapeutic amount when administer alone. In someembodiments, a therapeutic effective amount of a Varenicline is anamount that is a non-therapeutic amount when administer alone. In someembodiments, a therapeutic effective amount of a Tropisetron is anamount that is a suboptimal therapeutic amount when administer alone anda therapeutic effective amount of a Varenicline is an amount that is asuboptimal therapeutic amount when administer alone. In someembodiments, a therapeutic effective amount of a Tropisetron is anamount that is a non-therapeutic amount when administer alone and atherapeutic effective amount of a Varenicline is an amount that is anon-therapeutic amount when administer alone.

In one embodiment, a combined therapy comprising, consists essentiallyof, or consists of one or more activators of an alpha-7 nicotinicacetylcholine receptor activity having 5-HT₃ receptor inhibitoryactivity and one or more activators of 5-HT₃ receptor activity for usein treating a schizophrenic disorder. In aspects of this embodiment, acombined therapy comprising, consists essentially of, or consists of oneor more activators of an alpha-7 nicotinic acetylcholine receptoractivity having 5-HT₃ receptor inhibitory activity and one or moreactivators of 5-HT₃ receptor activity for use in treating aschizophrenia. In other aspects of this embodiment, a combined therapycomprising, consists essentially of, or consists of one or moreactivators of an alpha-7 nicotinic acetylcholine receptor activityhaving 5-HT₃ receptor inhibitory activity and one or more activators of5-HT₃ receptor activity for use in treating a treatment resistantschizophrenia. In yet other aspects of this embodiment, a combinedtherapy comprising, consists essentially of, or consists of one or moreactivators of an alpha-7 nicotinic acetylcholine receptor activityhaving 5-HT₃ receptor inhibitory activity and one or more activators of5-HT₃ receptor activity for use in treating cognitive impairmentassociated with schizophrenia.

In one embodiment, a combined therapy comprising, consists essentiallyof, or consists of a therapeutically effective amount of one or moreactivators of an alpha-7 nicotinic acetylcholine receptor activityhaving 5-HT₃ receptor inhibitory activity and a therapeuticallyeffective amount of one or more activators of 5-HT₃ receptor activityfor use in treating a schizophrenic disorder. In aspects of thisembodiment, a combined therapy comprising, consists essentially of, orconsists of a therapeutically effective amount of one or more activatorsof an alpha-7 nicotinic acetylcholine receptor activity having 5-HT₃receptor inhibitory activity and a therapeutically effective amount ofone or more activators of 5-HT₃ receptor activity for use in treating aschizophrenia. In other aspects of this embodiment, a combined therapycomprising, consists essentially of, or consists of a therapeuticallyeffective amount of one or more activators of an alpha-7 nicotinicacetylcholine receptor activity having 5-HT₃ receptor inhibitoryactivity and a therapeutically effective amount of one or moreactivators of 5-HT₃ receptor activity for use in treating a treatmentresistant schizophrenia. In yet other aspects of this embodiment, acombined therapy comprising, consists essentially of, or consists of atherapeutically effective amount of one or more activators of an alpha-7nicotinic acetylcholine receptor activity having 5-HT₃ receptorinhibitory activity and a therapeutically effective amount of one ormore activators of 5-HT₃ receptor activity for use in treating acognitive impairment associated with schizophrenia. In some embodiments,a therapeutic effective amount of one or more activators of an alpha-7nicotinic acetylcholine receptor activity having 5-HT₃ receptorinhibitory activity is an amount that is a suboptimal therapeutic amountwhen administer alone. In some embodiments, a therapeutic effectiveamount of one or more activators of an alpha-7 nicotinic acetylcholinereceptor activity having 5-HT₃ receptor inhibitory activity is an amountthat is a non-therapeutic amount when administer alone. In someembodiments, a therapeutic effective amount of one or more 5-HT₃receptor agonists is an amount that is a suboptimal therapeutic amountwhen administer alone. In some embodiments, a therapeutic effectiveamount of one or more 5-HT₃ receptor agonists is an amount that is anon-therapeutic amount when administer alone. In some embodiments, atherapeutic effective amount of one or more activators of an alpha-7nicotinic acetylcholine receptor activity having 5-HT₃ receptorinhibitory activity is an amount that is a suboptimal therapeutic amountwhen administer alone and a therapeutic effective amount of one or more5-HT₃ receptor agonists is an amount that is a suboptimal therapeuticamount when administer alone. In some embodiments, a therapeuticeffective amount of one or more activators of an alpha-7 nicotinicacetylcholine receptor activity having 5-HT₃ receptor inhibitoryactivity is an amount that is a non-therapeutic amount when administeralone and a therapeutic effective amount of one or more 5-HT₃ receptoragonists is an amount that is a non-therapeutic amount when administeralone.

In one embodiment, a combined therapy comprising, consists essentiallyof, or consists of one or more alpha-7 nicotinic acetylcholine receptoragonists having 5-HT₃ receptor antagonistic activity and one or more5-HT₃ receptor agonists for use in treating a schizophrenic disorder. Inaspects of this embodiment, a combined therapy comprising, consistsessentially of, or consists of one or more alpha-7 nicotinicacetylcholine receptor agonists having 5-HT₃ receptor antagonisticactivity and one or more 5-HT₃ receptor agonists for use in treating aschizophrenia. In other aspects of this embodiment, a combined therapycomprising, consists essentially of, or consists of one or more alpha-7nicotinic acetylcholine receptor agonists having 5-HT₃ receptorantagonistic activity and one or more 5-HT₃ receptor agonists for use intreating a treatment resistant schizophrenia. In yet other aspects ofthis embodiment, a combined therapy comprising, consists essentially of,or consists of one or more alpha-7 nicotinic acetylcholine receptoragonists having 5-HT₃ receptor antagonistic activity and one or more5-HT₃ receptor agonists for use in treating a cognitive impairmentassociated with schizophrenia.

In one embodiment, a combined therapy comprising, consists essentiallyof, or consists of a therapeutically effective amount of one or morealpha-7 nicotinic acetylcholine receptor agonists having 5-HT₃ receptorantagonistic activity and a therapeutically effective amount of one ormore 5-HT₃ receptor agonists for use in treating a schizophrenicdisorder. In aspects of this embodiment, a combined therapy comprising,consists essentially of, or consists of a therapeutically effectiveamount of one or more alpha-7 nicotinic acetylcholine receptor agonistshaving 5-HT₃ receptor antagonistic activity and a therapeuticallyeffective amount of one or more 5-HT₃ receptor agonists for use intreating a schizophrenia. In other aspects of this embodiment, acombined therapy comprising, consists essentially of, or consists of atherapeutically effective amount of one or more alpha-7 nicotinicacetylcholine receptor agonists having 5-HT₃ receptor antagonisticactivity and a therapeutically effective amount of one or more 5-HT₃receptor agonists for use in treating a treatment resistantschizophrenia. In yet other aspects of this embodiment, a combinedtherapy comprising, consists essentially of, or consists of atherapeutically effective amount of one or more alpha-7 nicotinicacetylcholine receptor agonists having 5-HT₃ receptor antagonisticactivity and a therapeutically effective amount of one or more 5-HT₃receptor agonists for use in treating a cognitive impairment associatedwith schizophrenia. In some embodiments, a therapeutic effective amountof one or more alpha-7 nicotinic acetylcholine receptor agonists having5-HT₃ receptor antagonistic activity is an amount that is a suboptimaltherapeutic amount when administer alone. In some embodiments, atherapeutic effective amount of one or more alpha-7 nicotinicacetylcholine receptor agonists having 5-HT₃ receptor antagonisticactivity is an amount that is a non-therapeutic amount when administeralone. In some embodiments, a therapeutic effective amount of one ormore 5-HT₃ receptor agonists is an amount that is a suboptimaltherapeutic amount when administer alone. In some embodiments, atherapeutic effective amount of one or more 5-HT₃ receptor agonists isan amount that is a non-therapeutic amount when administer alone. Insome embodiments, a therapeutic effective amount of one or more alpha-7nicotinic acetylcholine receptor agonists having 5-HT₃ receptorantagonistic activity is an amount that is a suboptimal therapeuticamount when administer alone and a therapeutic effective amount of oneor more 5-HT₃ receptor agonists is an amount that is a suboptimaltherapeutic amount when administer alone. In some embodiments, atherapeutic effective amount of one or more alpha-7 nicotinicacetylcholine receptor agonists having 5-HT₃ receptor antagonisticactivity is an amount that is a non-therapeutic amount when administeralone and a therapeutic effective amount of one or more 5-HT₃ receptoragonists is an amount that is a non-therapeutic amount when administeralone.

In one embodiment, a combined therapy comprising, consists essentiallyof, or consists of one or more alpha-7 nicotinic acetylcholine receptoragonists having 5-HT₃ receptor inverse agonistic activity and one ormore 5-HT₃ receptor agonists for use in treating a schizophrenicdisorder. In aspects of this embodiment, a combined therapy comprising,consists essentially of, or consists of one or more alpha-7 nicotinicacetylcholine receptor agonists having 5-HT₃ receptor inverse agonisticactivity and one or more 5-HT₃ receptor agonists for use in treating aschizophrenia. In other aspects of this embodiment, a combined therapycomprising, consists essentially of, or consists of one or more alpha-7nicotinic acetylcholine receptor agonists having 5-HT₃ receptor inverseagonistic activity and one or more 5-HT₃ receptor agonists for use intreating a treatment resistant schizophrenia. In yet other aspects ofthis embodiment, a combined therapy comprising, consists essentially of,or consists of one or more alpha-7 nicotinic acetylcholine receptoragonists having 5-HT₃ receptor inverse agonistic activity and one ormore 5-HT₃ receptor agonists for use in treating a cognitive impairmentassociated with schizophrenia.

In one embodiment, a combined therapy comprising, consists essentiallyof, or consists of a therapeutically effective amount of one or morealpha-7 nicotinic acetylcholine receptor agonists having 5-HT₃ receptorinverse agonistic activity and a therapeutically effective amount of oneor more 5-HT₃ receptor agonists for use in treating a schizophrenicdisorder. In aspects of this embodiment, a combined therapy comprising,consists essentially of, or consists of a therapeutically effectiveamount of one or more alpha-7 nicotinic acetylcholine receptor agonistshaving 5-HT₃ receptor inverse agonistic activity and a therapeuticallyeffective amount of one or more 5-HT₃ receptor agonists for use intreating a schizophrenia. In other aspects of this embodiment, acombined therapy comprising, consists essentially of, or consists of atherapeutically effective amount of one or more alpha-7 nicotinicacetylcholine receptor agonists having 5-HT₃ receptor inverse agonisticactivity and a therapeutically effective amount of one or more 5-HT₃receptor agonists for use in treating a treatment resistantschizophrenia. In yet other aspects of this embodiment, a combinedtherapy comprising, consists essentially of, or consists of atherapeutically effective amount of one or more alpha-7 nicotinicacetylcholine receptor agonists having 5-HT₃ receptor inverse agonisticactivity and a therapeutically effective amount of one or more 5-HT₃receptor agonists for use in treating a cognitive impairment associatedwith schizophrenia. In some embodiments, a therapeutic effective amountof one or more alpha-7 nicotinic acetylcholine receptor agonists having5-HT₃ receptor inverse agonistic activity is an amount that is asuboptimal therapeutic amount when administer alone. In someembodiments, a therapeutic effective amount of one or more alpha-7nicotinic acetylcholine receptor agonists having 5-HT₃ receptor inverseagonistic activity is an amount that is a non-therapeutic amount whenadminister alone. In some embodiments, a therapeutic effective amount ofone or more 5-HT₃ receptor agonists is an amount that is a suboptimaltherapeutic amount when administer alone. In some embodiments, atherapeutic effective amount of one or more 5-HT₃ receptor agonists isan amount that is a non-therapeutic amount when administer alone. Insome embodiments, a therapeutic effective amount of one or more alpha-7nicotinic acetylcholine receptor agonists having 5-HT₃ receptor inverseagonistic activity is an amount that is a suboptimal therapeutic amountwhen administer alone and a therapeutic effective amount of one or more5-HT₃ receptor agonists is an amount that is a suboptimal therapeuticamount when administer alone. In some embodiments, a therapeuticeffective amount of one or more alpha-7 nicotinic acetylcholine receptoragonists having 5-HT₃ receptor inverse agonistic activity is an amountthat is a non-therapeutic amount when administer alone and a therapeuticeffective amount of one or more 5-HT₃ receptor agonists is an amountthat is a non-therapeutic amount when administer alone.

In a preferred embodiment, a combined therapy comprising, consistsessentially of, or consists of Varenicline and Tropisetron for use intreating a schizophrenic disorder. In aspects of this embodiment, acombined therapy comprising, consists essentially of, or consists ofVarenicline and Tropisetron for use in treating a schizophrenia. Inother aspects of this embodiment, a combined therapy comprising,consists essentially of, or consists of Varenicline and Tropisetron foruse in treating a treatment resistant schizophrenia. In yet otheraspects of this embodiment, a combined therapy comprising, consistsessentially of, or consists of Varenicline and Tropisetron for use intreating a cognitive impairment associated with schizophrenia.

In a more preferred embodiment, a combined therapy comprising, consistsessentially of, or consists of a therapeutically effective amount ofVarenicline and a therapeutically effective amount of Tropisetron foruse in treating a schizophrenic disorder. In aspects of this embodiment,a combined therapy comprising, consists essentially of, or consists of atherapeutically effective amount of Varenicline and a therapeuticallyeffective amount of Tropisetron for use in treating a schizophrenia. Inother aspects of this embodiment, a combined therapy comprising,consists essentially of, or consists of a therapeutically effectiveamount of Varenicline and a therapeutically effective amount ofTropisetron for use in treating a treatment resistant schizophrenia. Inyet other aspects of this embodiment, a combined therapy comprising,consists essentially of, or consists of a therapeutically effectiveamount of Varenicline and a therapeutically effective amount ofTropisetron for use in treating a cognitive impairment associated withschizophrenia. In some embodiments, a therapeutic effective amount of aTropisetron is an amount that is a suboptimal therapeutic amount whenadminister alone. In some embodiments, a therapeutic effective amount ofa Tropisetron is an amount that is a non-therapeutic amount whenadminister alone. In some embodiments, a therapeutic effective amount ofa Varenicline is an amount that is a suboptimal therapeutic amount whenadminister alone. In some embodiments, a therapeutic effective amount ofa Varenicline is an amount that is a non-therapeutic amount whenadminister alone. In some embodiments, a therapeutic effective amount ofa Tropisetron is an amount that is a suboptimal therapeutic amount whenadminister alone and a therapeutic effective amount of a Varenicline isan amount that is a suboptimal therapeutic amount when administer alone.In some embodiments, a therapeutic effective amount of a Tropisetron isan amount that is a non-therapeutic amount when administer alone and atherapeutic effective amount of a Varenicline is an amount that is anon-therapeutic amount when administer alone.

Aspects of the present specification can also be described as follows:

-   1. A method of treating a schizophrenic disorder by administering a    combined therapy comprising one or more activators of an alpha-7    nicotinic acetylcholine receptor activity having 5-HT₃ receptor    inhibitory activity and one or more activators of 5-HT₃ receptor    activity.-   2. The method of embodiment 1, wherein the one or more activators of    an alpha-7 nicotinic acetylcholine receptor activity comprise one or    more alpha-7 nicotinic acetylcholine receptor agonists, one or more    positive allosteric modulators of an alpha-7 nicotinic acetylcholine    receptor activity, or a combination thereof.-   3. The method of embodiment 2, wherein the one or more alpha-7    nicotinic acetylcholine receptor agonists include an alpha-7    nicotinic acetylcholine receptor full agonist, an alpha-7 nicotinic    acetylcholine receptor partial agonist, or an alpha-7 nicotinic    acetylcholine receptor co-agonist.-   4. The method of embodiment 2 or 3, wherein the one or more alpha-7    nicotinic acetylcholine receptor agonists include an alpha-7    nicotinic acetylcholine receptor pan agonist or an alpha-7 nicotinic    acetylcholine receptor selective agonist.-   5. The method of embodiment 2, wherein the one or more alpha-7    nicotinic acetylcholine receptor agonists include    (+)-N-(1-azabicyclo[2.2.2]oct-3-yl)benzo[b]furan-2-carboxamide,    A-582941, Acetylcholine, Amyloid beta, Anabasine, AR-R17779,    Bradanicline, Choline, Encenicline, Epiboxidine, GTS-21, ICH-3,    Nicotine, PHA-543,613, PHA-709829, PNU-282,987, SSR-180,711,    TC-1698, Tilorone, Tropisetron, WAY-317,538, or any combination    thereof.-   6. The method of embodiment 2, wherein the one or more positive    allosteric modulators of an alpha-7 nicotinic acetylcholine receptor    activity include A-867744, AVL-3288, Galantamine, Ivermectin,    Nefiracetam, NS-1738, PNU-120,596, or any combination thereof.-   7. The method of any one of embodiments 1-6, wherein the 5-HT₃    receptor inhibitory activity comprise a 5-HT₃ receptor antagonistic    activity, a 5-HT₃ receptor inverse agonistic activity, or a    combination thereof.-   8. The method of embodiment 7, wherein the 5-HT₃ receptor    antagonistic activity is a 5-HT₃ receptor full antagonistic    activity, a 5-HT₃ receptor partial antagonistic activity, or a 5-HT₃    receptor co-antagonistic activity.-   9. The method of embodiment 7 or 8, wherein the 5-HT₃ receptor    antagonistic activity is a 5-HT₃ receptor pan antagonistic activity    or a 5-HT₃ receptor selective antagonistic activity.-   10. The method of any one of embodiment 7-9, wherein the 5-HT₃    receptor antagonistic activity includes an antidepressant 5-HT₃    receptor antagonistic activity, an antiemetic 5-HT₃ receptor    antagonistic activity, an antimalarial 5-HT₃ receptor antagonistic    activity, an antipsychotic 5-HT₃ receptor antagonistic activity, a    gastroprokinetic 5-HT₃ receptor antagonistic activity, or any    combination thereof.-   11. The method of embodiment 2, wherein the 5-HT₃ receptor inverse    agonistic activity is a 5-HT₃ receptor full inverse agonistic    activity, a 5-HT₃ receptor partial inverse agonistic activity, or a    5-HT₃ receptor co-inverse agonistic activity.-   12. The method of embodiment 2 or 11, wherein the 5-HT₃ receptor    inverse agonistic activity is a 5-HT₃ receptor pan inverse agonistic    activity or a 5-HT₃ receptor selective inverse agonistic activity.-   13. The method of any one of embodiments 1-12, wherein the one or    more activators of 5-HT₃ receptor activity comprise one or more    5-HT₃ receptor agonists.-   14. The method of embodiment 13, wherein the one or more 5-HT₃    receptor agonists include a 5-HT₃ receptor full agonist, a 5-HT₃    receptor partial agonist, a 5-HT₃ receptor co-agonist or a 5-HT₃    receptor super-agonist.-   15. The method of embodiment 13 or 14, wherein the one or more 5-HT₃    receptor agonists include a 5-HT₃ receptor pan agonist or a 5-HT₃    receptor selective agonist.-   16. The method of any one of embodiments 13-15, wherein the one or    more 5-HT₃ receptor agonists have an alpha-7 nicotinic acetylcholine    receptor agonistic activity.-   17. The method of any one of embodiments 13-16, wherein the one or    more 5-HT₃ receptor agonists include an alcohol having 5-HT₃    receptor agonist activity, meta-Chlorophenylbiguanide    (1-(3-Chlorophenylbiguanide)), Ibogaine, Phenylbiguanide, a    piperazine having 5-HT₃ receptor agonist activity, RS-56812    (N-(1-Azabicyclo[2.2.2]octan-3-yl)-2-(1-methylindol-3-yl)-2-oxoacetamide),    Serotonin, SR-57227 (1-(6-Chloropyridin-2-yl)piperidin-4-amine),    SR-57227A (4-Amino-1-(6-chloro-2-pyridyl)-piperidine hydrochloride),    a tryptamine having 5-HT₃ receptor agonist activity, Varenicline, a    volatile gas having 5-HT₃ receptor agonist activity, and YM-31636    (2-(1H-imidazol-4-ylmethyl)-8H-indeno[1,2-d]thiazole).-   18. The method of embodiment 17, wherein the alcohol having 5-HT₃    receptor agonist activity includes butanol, ethanol, or    trichloroethanol.-   19. The method of embodiment 17, wherein the piperazine having 5-HT₃    receptor agonist activity includes benzylpiperazine,    meta-Chlorophenylpiperazine, or quipazine.-   20. The method of embodiment 17, wherein the tryptamine having 5-HT₃    receptor agonist activity includes 2-methyl-5-hydroxytryptamine,    α-Methyltryptamine, 5-carboxamidotryptamine,    N,N-Dimethyl-5-hydroxytryptamine (Bufotenin), or    5-hydroxy-N,N,N-trimethyltryptammonium (bufotenidine).-   21. The method of embodiment 17, wherein the volatile gas having    5-HT₃ receptor agonist activity includes halothane, isoflurane,    toluene, or trichloroethane.-   22. The method of embodiment 1, wherein the one or more activators    of an alpha-7 nicotinic acetylcholine receptor activity is    Tropisetron and the one or more activators of 5-HT₃ receptor    activity is Varenicline.-   23. The method of any one of embodiments 2-4, and 13-16 wherein the    one or more alpha-7 nicotinic acetylcholine receptor agonists is    Tropisetron and the one or more 5-HT₃ receptor agonists is    Varenicline.-   24. The method of any one of embodiments 1-23, wherein the one or    more activators of an alpha-7 nicotinic acetylcholine receptor    activity and the one or more activators of 5-HT₃ receptor activity    are provided in a therapeutic effective amount.-   25. The method of any one of embodiments 2-23, wherein the one or    more alpha-7 nicotinic acetylcholine receptor agonists, one or more    positive allosteric modulators of an alpha-7 nicotinic acetylcholine    receptor activity and/or the one or more 5-HT₃ receptor agonists are    provided in a therapeutic effective amount.-   26. The method of any one of embodiments 1-25, wherein the    combination therapy comprises administration of a first composition    comprising one or more activators of an alpha-7 nicotinic    acetylcholine receptor activity and a second composition comprising    one or more activators of 5-HT₃ receptor activity.-   27. The method of any one of embodiments 1-25, wherein the    combination therapy comprises administration of a single composition    comprising one or more activators of an alpha-7 nicotinic    acetylcholine receptor activity and one or more activators of 5-HT₃    receptor activity.-   28. The method of any one of embodiments 2-25, wherein the    combination therapy comprises administration of a first composition    comprising one or more alpha-7 nicotinic acetylcholine receptor    agonists and/or one or more positive allosteric modulators of an    alpha-7 nicotinic acetylcholine receptor activity and a second    composition comprising one or more 5-HT₃ receptor agonists.-   29. The method of any one of embodiments 2-25, wherein the    combination therapy comprises administration of a single composition    comprising one or more alpha-7 nicotinic acetylcholine receptor    agonists and/or one or more positive allosteric modulators of an    alpha-7 nicotinic acetylcholine receptor activity and one or more    5-HT₃ receptor agonists.-   30. A combined therapy comprising one or more activators of an    alpha-7 nicotinic acetylcholine receptor activity having 5-HT₃    receptor inhibitory activity and one or more activators of 5-HT₃    receptor activity for use in treating a schizophrenic disorder.-   31. The combined therapy of embodiment 30, wherein the one or more    activators of an alpha-7 nicotinic acetylcholine receptor activity    comprise one or more alpha-7 nicotinic acetylcholine receptor    agonists, one or more positive allosteric modulators of an alpha-7    nicotinic acetylcholine receptor activity, or a combination thereof.-   32. The combined therapy of embodiment 31, wherein the one or more    alpha-7 nicotinic acetylcholine receptor agonists include an alpha-7    nicotinic acetylcholine receptor full agonist, an alpha-7 nicotinic    acetylcholine receptor partial agonist, or an alpha-7 nicotinic    acetylcholine receptor co-agonist.-   33. The combined therapy of embodiment 31 or 32, wherein the one or    more alpha-7 nicotinic acetylcholine receptor agonists includes an    alpha-7 nicotinic acetylcholine receptor pan agonist or an alpha-7    nicotinic acetylcholine receptor selective agonist.-   34. The combined therapy of embodiment 31, wherein the one or more    alpha-7 nicotinic acetylcholine receptor agonists include    (+)-N-(1-azabicyclo[2.2.2]oct-3-yl)benzo[b]furan-2-carboxamide,    A-582941, Acetylcholine, Amyloid beta, Anabasine, AR-R17779,    Bradanicline, Choline, Encenicline, Epiboxidine, GTS-21, ICH-3,    Nicotine, PHA-543,613, PHA-709829, PNU-282,987, SSR-180,711,    TC-1698, Tilorone, Tropisetron, WAY-317,538, or any combination    thereof.-   35. The combined therapy of embodiment 31, wherein the one or more    positive allosteric modulators of an alpha-7 nicotinic acetylcholine    receptor activity include A-867744, AVL-3288, Galantamine,    Ivermectin, Nefiracetam, NS-1738, PNU-120,596, or any combination    thereof.-   36. The combined therapy of any one of embodiments 30-35, wherein    the 5-HT₃ receptor inhibitory activity comprise a 5-HT₃ receptor    antagonistic activity, a 5-HT₃ receptor inverse agonistic activity,    or a combination thereof.-   37. The combined therapy of embodiment 36, wherein the 5-HT₃    receptor antagonistic activity is a 5-HT₃ receptor full antagonistic    activity, a 5-HT₃ receptor partial antagonistic activity, or a 5-HT₃    receptor co-antagonistic activity.-   38. The combined therapy of embodiment 36 or 37, wherein the 5-HT₃    receptor antagonistic activity is a 5-HT₃ receptor pan antagonistic    activity or a 5-HT₃ receptor selective antagonistic activity.-   39. The combined therapy of any one of embodiment 36-38, wherein the    5-HT₃ receptor antagonistic activity includes an antidepressant    5-HT₃ receptor antagonistic activity, an antiemetic 5-HT₃ receptor    antagonistic activity, an antimalarial 5-HT₃ receptor antagonistic    activity, an antipsychotic 5-HT₃ receptor antagonistic activity, a    gastroprokinetic 5-HT₃ receptor antagonistic activity, or any    combination thereof.-   40. The combined therapy of embodiment 30, wherein the 5-HT₃    receptor inverse agonistic activity is a 5-HT₃ receptor full inverse    agonistic activity, a 5-HT₃ receptor partial inverse agonistic    activity, or a 5-HT₃ receptor co-inverse agonistic activity.-   41. The combined therapy of embodiment 30 or 40, wherein the 5-HT₃    receptor agonistic activity is a 5-HT₃ receptor pan inverse    agonistic activity or a 5-HT₃ receptor selective inverse agonistic    activity.-   42. The combined therapy of any one of embodiments 30-41, wherein    the one or more activators of 5-HT₃ receptor activity comprise one    or more 5-HT₃ receptor agonists.-   43. The combined therapy of embodiment 42, wherein the 5-HT₃    receptor agonist is a 5-HT₃ receptor full agonist, a 5-HT₃ receptor    partial agonist, a 5-HT₃ receptor co-agonist or a 5-HT₃ receptor    super-agonist.-   44. The combined therapy of embodiment 42 or 43, wherein the 5-HT₃    receptor agonist is a 5-HT₃ receptor pan agonist or a 5-HT₃ receptor    selective agonist.-   45. The combined therapy of any one of embodiments 42-44, wherein    the one or more 5-HT₃ receptor agonists have an alpha-7 nicotinic    acetylcholine receptor agonistic activity.-   46. The combined therapy of any one of embodiment 42-45, wherein the    one or more 5-HT₃ receptor agonists is an alcohol having 5-HT₃    receptor agonist activity, meta-Chlorophenylbiguanide    (1-(3-Chlorophenylbiguanide)), Ibogaine, Phenylbiguanide, a    piperazine having 5-HT₃ receptor agonist activity, RS-56812    (N-(1-Azabicyclo[2.2.2]octan-3-yl)-2-(1-methylindol-3-yl)-2-oxoacetamide),    Serotonin, SR-57227 (1-(6-Chloropyridin-2-yl)piperidin-4-amine),    SR-57227A (4-Amino-1-(6-chloro-2-pyridyl)-piperidine hydrochloride),    a tryptamine having 5-HT₃ receptor agonist activity, Varenicline, a    volatile gas having 5-HT₃ receptor agonist activity, and YM-31636    (2-(1H-imidazol-4-ylmethyl)-8H-indeno[1,2-d]thiazole).-   47. The combined therapy of embodiment 46, wherein the alcohol    having 5-HT₃ receptor agonist activity includes butanol, ethanol, or    trichloroethanol.-   48. The combined therapy of embodiment 46, wherein the piperazine    having 5-HT₃ receptor agonist activity includes benzylpiperazine,    meta-Chlorophenylpiperazine, or quipazine.-   49. The combined therapy of embodiment 46, wherein the tryptamine    having 5-HT₃ receptor agonist activity includes    2-methyl-5-hydroxytryptamine, α-Methyltryptamine,    5-carboxamidotryptamine, N,N-Dimethyl-5-hydroxytryptamine    (Bufotenin), or 5-hydroxy-N,N,N-trimethyltryptammonium    (bufotenidine).-   50. The combined therapy of embodiment 46, wherein the volatile gas    having 5-HT₃ receptor agonist activity includes halothane,    isoflurane, toluene, or trichloroethane.-   51. The combined therapy of embodiment 30, wherein the one or more    activators of an alpha-7 nicotinic acetylcholine receptor activity    is Tropisetron and the one or more activators of 5-HT₃ receptor    activity is Varenicline.-   52. The combined therapy of any one of embodiments 31-33 and 42-45    wherein the one or more alpha-7 nicotinic acetylcholine receptor    agonists is Tropisetron and the one or more 5-HT₃ receptor agonists    is Varenicline.-   53. The combined therapy of any one of embodiments 30-52, wherein    the one or more activators of an alpha-7 nicotinic acetylcholine    receptor activity and the one or more activators of 5-HT₃ receptor    activity are provided in a therapeutic effective amount.-   54. The combined therapy of any one of embodiments 31-52, wherein    the one or more alpha-7 nicotinic acetylcholine receptor agonists,    one or more positive allosteric modulators of an alpha-7 nicotinic    acetylcholine receptor activity, and/or the one or more 5-HT₃    receptor agonists are provided in a therapeutic effective amount.-   55. The combined therapy of any one of embodiments 30-54, wherein    the combination therapy comprises administration of a first    composition comprising one or more activators of an alpha-7    nicotinic acetylcholine receptor activity and a second composition    comprising one or more activators of 5-HT₃ receptor activity.-   56. The combined therapy of any one of embodiments 30-54, wherein    the combination therapy comprises administration of a single    composition comprising one or more activators of an alpha-7    nicotinic acetylcholine receptor activity and one or more activators    of 5-HT₃ receptor activity.-   57. The combined therapy of any one of embodiments 31-54, wherein    the combination therapy comprises administration of a first    composition comprising one or more alpha-7 nicotinic acetylcholine    receptor agonists and/or one or more positive allosteric modulators    of an alpha-7 nicotinic acetylcholine receptor activity and a second    composition comprising one or more 5-HT₃ receptor agonists.-   58. The combined therapy of any one of embodiments 31-54, wherein    the combination therapy comprises administration of a single    composition comprising one or more alpha-7 nicotinic acetylcholine    receptor agonists and/or one or more positive allosteric modulators    of an alpha-7 nicotinic acetylcholine receptor activity, and one or    more 5-HT₃ receptor agonists.-   59. The method of any one of embodiments 1-29 or the combined    therapy of any one of embodiments 30-58, wherein the schizophrenic    disorder is a schizophrenia, a schizophreniform disorder,    schizoaffective disorder, or a schizotypal personality disorder.-   60. The method of embodiment 69 or the combined therapy of    embodiment 69, wherein the schizophrenia is a disorganized    schizophrenia, a catatonic schizophrenia, a paranoid schizophrenia,    an undifferentiated schizophrenia, or a residual schizophrenia.-   61. The method of embodiment 69 or the combined therapy of    embodiment 69, wherein the schizophrenia is a ultra-high risk (UHR)    or at risk mental state (ARMS) for psychosis, a first-episode    psychosis, a chronic treatment responsive schizophrenia, a treatment    resistant schizophrenia or a cognitive impaired schizophrenia.-   62. A method of treating a schizophrenic disorder comprises,    consists essentially of, or consists of administering a combined    therapy comprising, consisting essentially of, or consisting of a    therapeutically effective amount of Varenicline and a    therapeutically effective amount of Tropisetron.-   63. A method of treating a schizophrenia comprises, consists    essentially of, or consists of administering a combined therapy    comprising, consisting essentially of, or consisting of a    therapeutically effective amount of Varenicline and a    therapeutically effective amount of Tropisetron.-   64. A method of treating a treatment resistant schizophrenia    comprises, consists essentially of, or consists of administering a    combined therapy comprising, consisting essentially of, or    consisting of a therapeutically effective amount of Varenicline and    a therapeutically effective amount of Tropisetron.-   65. A method of treating a cognitive impaired schizophrenia    comprises, consists essentially of, or consists of administering a    combined therapy comprising, consisting essentially of, or    consisting of a therapeutically effective amount of Varenicline and    a therapeutically effective amount of Tropisetron.-   66. A combined therapy comprising, consists essentially of, or    consists of a therapeutically effective amount of Varenicline and a    therapeutically effective amount of Tropisetron for use in treating    a schizophrenic disorder.-   67. A combined therapy comprising, consists essentially of, or    consists of a therapeutically effective amount of Varenicline and a    therapeutically effective amount of Tropisetron for use in treating    a schizophrenia.-   68. A combined therapy comprising, consists essentially of, or    consists of a therapeutically effective amount of Varenicline and a    therapeutically effective amount of Tropisetron for use in treating    a treatment resistant schizophrenia.-   69. A combined therapy comprising, consists essentially of, or    consists of a therapeutically effective amount of Varenicline and a    therapeutically effective amount of Tropisetron for use in treating    a cognitive impaired schizophrenia.

EXAMPLES

The following non-limiting examples are provided for illustrativepurposes only in order to facilitate a more complete understanding ofrepresentative embodiments now contemplated. These examples should notbe construed to limit any of the embodiments described in the presentspecification, including those pertaining to the active agents,combination therapy, or methods or uses of treating a schizophrenicdisorder disclosed herein.

Example 1 In Vivo Efficacy Study

This example shows the efficacy of a combination therapy comprising oneor more activators of an alpha-7 nicotinic acetylcholine receptoractivity having 5-HT₃ receptor inhibitory activity and one or moreactivators of 5-HT₃ receptor activity for use in treating aschizophrenic disorder.

Tropisetron is an alpha-7 nicotinic acetylcholine receptor activityhaving 5-HT₃ receptor inhibitory activity. As a potent anti-emetic,Tropisetron is used primarily in the treatment of patients withchemotherapy-induced or postoperative nausea and vomiting. With alpha-7nicotinic acetylcholine receptors located in many brain areas importantfor cognition (including the hippocampus and frontal cortex), thealpha-7 nicotinic acetylcholine receptor activity of Tropisetron couldpotentially help modulate brain activity. Although some pro-cognitiveeffects in patients with schizophrenia have been seen, the therapeuticusefulness of Tropisetron in cognitive disorders is not feasible. First,Tropisetron is a peripheral, dose-response active ingredient since it isalmost completely absorbed from the gastrointestinal tract. Second,Tropisetron is not suitable for chronic administration due to off-targetgastrointestinal activity side effects that include a reduction in guttransit and constipation due to the 5-HT₃ receptor inhibitory activityof Tropisertron. Without wishing to be limited by any theory, theaddition of, could substantially improve the tolerability of Tropisetronby off-setting peripheral side effects via stimulation of 5-HT3 in theGI tract. In addition, Varenicline itself has alpha-7 nicotinicacetylcholine receptor activity which can significantly enhance thetherapeutic effect of Tropisertron. Thus, the combined administration ofboth these compounds would positively affect cognition whilst minimizingunwanted serotonergic-induced gastrointestinal side effects.

Normal male lister-hooded rats will be used to investigate latentinhibition based upon conditioned suppression of a lever press responsefor reward. Animals will initially undergo handling and habituation overa period of two-weeks followed by mild food restriction and initialtraining in the lever press response. Following 10 days lever traininganimals will be tested using a latent inhibition assay. This will beconducted over four consecutive days as follows: Day 1 will compriseconducting pre-exposure (PE) or control non pre-exposure (NPE) phases onanimals; Day 2 will comprise conditioning animals using foot-shockconditioning regime (0.3 mA, 1 sec exposure); Day 3 will comprisere-baseline of animals; and Day 4 will comprise conducting a test phaseon animals.

An amphetamine induced latent inhibition study will then be performed. Apreclinical latent inhibition assay will be conducted as described inU.S. Provisional Patent Application Ser. No. 62/820,490, filed on Mar.19, 2019 and titled “Method and Uses of Diagnosing and RecommendingTreatment for a Psychotic Disorder”, which is hereby incorporated byreference in its entirety, except that the assay will be modified foranimal assessment as discussed herein. In this study, control (NPE)animals will be compared to animals pre-exposed to the foot-shockconditioning cue following vehicle or amphetamine treatment (n=8 pergroup, 4 groups). This study will confirm the dose of amphetaminerequired to induce an optimal latent inhibition effect for subsequenttesting in combination with the novel compounds.

Following an amphetamine induced latent inhibition study, adose-response study using an alpha-7 nicotinic acetylcholine receptoractivity having 5-HT₃ receptor inhibitory activity or 5-HT₃ receptoragonist will be performed. This 12-week study will test the ability of asingle agent to attenuate an amphetamine-induced deficit in latentinhibition. Each active agent will be evaluated at three doses based oncurrent pharmacokinetic and clinical data and compared to vehiclecontrol. Each active agent test group will be divided into fourtreatment groups (n=12) as follows: 1) alpha-7 nicotinic acetylcholinereceptor activity having 5-HT₃ receptor inhibitory activity treatedgroup comprising placebo/placebo animals; placebo/Tropisetron dose 1animals; placebo/Tropisetron dose 2 animals; placebo/Tropisetron dose 3animals; and 2) 5-HT₃ receptor agonist treated group compriseplacebo/placebo animals; placebo/varenicline dose 1 animals;placebo/varenicline dose 2 animals; placebo/varenicline dose 3 animals.

Following a dose-response study, a combination therapy study will beperformed using the optimal therapeutically effective amount of analpha-7 nicotinic acetylcholine receptor activity having 5-HT₃ receptorinhibitory activity and 5-HT₃ receptor agonist as determined in adose-response study. This 6-week study will demonstrate the efficacy ofa combination therapy using an alpha-7 nicotinic acetylcholine receptoractivity having 5-HT₃ receptor inhibitory activity and 5-HT₃ receptoragonist compared to either active agent alone. Each treatment group(n=12) will be tested at a single dose in amphetamine-treated animalsand compared to an amphetamine plus vehicle treated group (n=12) asfollows: 1) alpha-7 nicotinic acetylcholine receptor activity having5-HT₃ receptor inhibitory activity alone treated group comprisinganimals treated with a single optimal effective therapeutic amount ofTropisetron; 2) 5-HT₃ receptor agonist alone treated group comprisinganimals treated with a single optimal effective therapeutic amount ofVarenicline; 3) combination therapy treated group comprising animalstreated with a single optimal effective therapeutic amount of bothTropisetron and Varenicline; and 4) control group comprising animalstreated with Amphetamine and vehicle.

Example 2 In Vivo Efficacy Study

This example shows the efficacy of a combination therapy comprising oneor more activators of an alpha-7 nicotinic acetylcholine receptoractivity having 5-HT₃ receptor inhibitory activity and one or moreactivators of 5-HT₃ receptor activity for use in treating aschizophrenic disorder.

C57BL/6 mice will be used to investigate latent inhibition (LI)conditioned emotional response cessation of drinking model in mice asdescribed in, e.g., Bay-Richter, et al., Enhanced Latent Inhibition inDopamine Receptor-Deficient Mice is Sex-Specific for the D1 but not D2Receptor Subtype: Implications for Antipsychotic Drug Action, Int. J.Neuropsychopharmacol. 12(3): 403-414 (2009); Bay-Richter, et al.,D-Amphetamine and Antipsychotic Drug Effects on Latent Inhibition inMice Lacking Dopamine D2 Receptors, Neuropsychopharmacology 38(8):1512-1520 (2013); O'Callaghan, et al., Potentiation of Latent Inhibitionby Haloperidol and Clozapine is Attenuated in Dopamine D2 Receptor(Drd-2)-Deficient Mice: Do Antipsychotics Influence Learning to IgnoreIrrelevant Stimuli via Both Drd-2 and Non-Drd-2 Mechanisms?, J.Psychopharmacol. 28(10): 973-977 (2014), each of which are herebyincorporated by reference in its entirety. Animals will initiallyundergo handling and habituation over a period of one-week where micewill be water restricted for 23 hours per day with one-hour free accessto water. On Day 1 to Day 6, animals will undergo lick training wheremice will have access to water in a chamber for 15 minutes and thenumber of licks per animal will be recorded. On Day 7 (pre-exposure)mice will be placed in a testing chamber with access to water withdrawn.One group will receive 20 presentations [determined from priorexperiments to produce reduced LI in controls] of a 5 second 85 dB tonewith a 15 second inter-stimulus interval (pre-exposed group, PE); acontrol group of non-pre-exposed (NPE) mice will be placed in a testingchamber with access to water withdrawn for an identical period of timebut will not receive a tone pre-exposure. On Day 8 (conditioning) micewill be placed in a testing chamber with access to water withdrawn.After two minutes, two tone-footshock pairings will be presented. Tonesare of 5 second duration and followed by a 1 second 0.38 mA footshockwith an inter-trial-interval of 2.5 minutes. Mice will remain in thechamber for 2.5 minutes following the second shock presentation. On Day16-17 (re-baseline) mice will be placed in a testing chamber for 15minute and given free access to water to re-establish stable licking,criterion will be that mice that did not complete more than 300 lickscontinuously will not continue to the test stage. On Day 18 (Test) micewill be placed in a testing chamber with free access to water. Number oflicks for each animal will be recorded and time taken to complete 80-90licks (A) and 90-100 licks (B) recorded. After completion of 90 licks, a5 second 85 dB tone will be presented until an animal reaches 100 licksor 600 seconds had elapsed. A suppression ratio (SR) will be calculatedaccording to the formula A/(A+B) yielding a scale of 0 to 0.5. Low SRindicates increased suppression of drinking; high SR indicates decreasedsuppression of drinking. LI is seen as higher SR in PE versus NPEgroups.

In one series of experiments, procognitive doses of Tropisetron andVarenicline will be established using a standard latent inhibition testof attention (as described above) in mice. Animals will be divided intoeight groups of 15 animals each (120 total mice), and two series ofexperiments of 60 animals per experiment will be conducted. In the firstexperimental series, the effects of Tropisteron on latent inhibitionwill be assessed at three different doses (Table 1). In the secondexperimental series the effects of Varenicline on latent inhibition willbe assessed at three different doses (Table 2). The results of theseexperiments will establish procognitive doses of Tropisteron andVarenicline that will potentiate low levels of latent inhibition. Theseresults will also enable the identification of suboptimal doses ofTropisetron and/or Varenicline. Gut motility will also be evaluated forsafety purposes.

TABLE 1 Experimental Series 1 Non-Preexposed (NPE) Pre-Exposed (PE)Group 1 Vehicle = placebo Group 5 Vehicle = placebo Group 2 Dose 1Tropisetron Group 6 Dose 1 Tropisetron Group 3 Dose 2 Tropisteron Group7 Dose 2 Tropisetron Group 4 Dose 3 Tropisteron Group 8 Dose 3Tropistron

TABLE 2 Experimental Series 2 Non-Preexposed (NPE) Pre-Exposed (PE)Group 1 Vehicle = Placebo Group 5 Vehicle = Placebo Group 2 Dose 1Varenicline Group 6 Dose 1 Varenicline Group 3 Dose 2 Varenicline Group7 Dose 2 Varenicline Group 4 Dose 3 Varenicline Group 8 Dose 3Varenicline

Ina third series of experiments, a combined Tropisetron and Vareniclinetreatment that potentiates the procognitive effects in latent inhibitionwill be determined. Animals will be divided into eight groups of 15animals each (120 total mice), and two series of experiments of 60animals will be conducted using the 18-day latent inhibition protocoldiscussed above. In both experimental series the effects of Tropisteronalone, Varenicline alone and a combined Tropisetron and Vareniclinetreatment on latent inhibition will be assessed (Table 3). The resultsof these experiments will establish that a combined Tropisteron andVarenicline treatment with each drug will potentiate the pro-cognitiveeffects in latent inhibition, compared to either drug administeredalone. Gut motility will also be evaluated for safety purposes.

TABLE 3 Experimental Series 3 Non-Preexposed (NPE) Pre-Exposed (PE)Group 1 Vehicle = placebo Group 5 Vehicle = placebo Group 2 TropisetronGroup 6 Tropisetron Group 3 Varenicline Group 7 Varenicline Group 4Tropisteron + Varenicline Group 8 Tropisteron + Varenicline

In a fourth series of experiments, a reversal of D-amphetamine induceddisruption of latent inhibition using a combined Tropisetron andVarenicline treatment will be assessed. Animals will be divided into tengroups of 15 animals each (150 total mice), and two series ofexperiments of 72 animals will be conducted using the 18-day latentinhibition protocol discussed above. In both experimental series theeffects of Tropisteron alone, Varenicline alone and a combinedTropisetron and Varenicline treatment, in the presence of D-amphetamine,on latent inhibition will be assessed (Table 4). The results of theseexperiments will establish that a combined Tropisetron and Vareniclinetreatment reverses D-amphetamine induced disruption of latentinhibition. Gut motility will also be evaluated for safety purposes.

TABLE 4 Experimental Series 4 Non-Preexposed (NPE) Pre-Exposed (PE)Group 1 Vehicle = placebo Group 6 Vehicle = placebo Group 2D-amphetamine Group 7 D-amphetamine Group 3 D-amphetamine + Group 8D-amphetamine + Tropisteron + Varenicline Tropisteron + VareniclineGroup 4 Tropisetron Group 9 Tropisetron Group 5 Varenicline Group 10Varenicline

In a fifth series of experiments, the optimal dose of MK801 that is ableto produce abnormally persistent latent inhibition will be assessed.Animals will be divided into eight groups of 15 animals each (120 totalmice), and the latent inhibition protocol discussed above will be used,except that there will be 4 tone-shock pairings administered to producelow LI (to then be reversed and potentiated by MK801). The effects ofMK801 on latent inhibition will be assessed at two different doses andin the presence of Clozapine (Table 5). The results of experiment 5 willestablish the optimal dose of MK801 that is able to produce abnormallypersistent latent inhibition before moving onto experiment 6.

TABLE 5 Experimental Series 5 Non-Preexposed (NPE) Pre-Exposed (PE)Group 1 Vehicle = placebo Group 5 Vehicle = placebo Group 2 Dose 1 MK801Group 6 Dose 1 MK801 Group 3 Dose 2 MK801 Group 7 Dose 2 MK801 Group 4MK801 + Clozapine Group 8 MK801 + Clozapine

In a sixth series of experiments, the ability of the combinedTropisetron and Varenicline treatment to reverse the MK801 inducedabnormally persistent latent inhibition effect will be assessed. Animalswill be divided into ten groups of 15 animals each (150 total mice), andthe latent inhibition protocol discussed above will be used, as perexperiment 5 with 4 tone-shock pairings administered to produce low LI.The effects of Tropisteron alone, Varenicline alone and a combinedTropisetron and Varenicline treatment in the presence of MK801 on latentinhibition will be assessed (Table 6). The results of this experimentwill establish that a combined Tropisetron and Varenicline treatmentreverses an MK801 induced abnormally persistent effect of latentinhibition. Gut motility will also be evaluated for safety purposes.

TABLE 6 Experimental Series 6 Non-Preexposed (NPE) Pre-Exposed (PE)Group 1 Vehicle = placebo Group 6 Vehicle = placebo Group 2 MK801 Group7 MK801 Group 3 MK801 + Group 8 MK801 + Tropisteron + VareniclineTropisteron + Varenicline Group 4 Tropisetron Group 9 Tropisetron Group5 Varenicline Group 10 Varenicline

In closing, it is to be understood that, although aspects of the presentspecification are highlighted by referring to specific embodiments, oneskilled in the art will readily appreciate that these describedembodiments are only illustrative of the principles of the subjectmatter disclosed herein. The specific embodiments are not intended to beexhaustive or to limit the invention to the precise forms disclosed.Therefore, it should be understood that the disclosed subject matter isin no way limited to a particular compound, composition, article,apparatus, methodology, protocol, and/or reagent, etc., describedherein, unless expressly stated as such. In addition, those of ordinaryskill in the art will recognize that certain changes, modifications,permutations, alterations, additions, subtractions and sub-combinationsthereof can be made in accordance with the teachings herein withoutdeparting from the spirit of the present specification. It is thereforeintended that the scope of the invention is not to be limited by thisdetailed description. Furthermore, it is intended that the followingappended claims and claims hereafter introduced are interpreted toinclude all such changes, modifications, permutations, alterations,additions, subtractions and sub-combinations as are within their truespirit and scope.

Certain embodiments of the present invention are described herein,including the best mode known to the inventors for carrying out theinvention. Of course, variations on these described embodiments willbecome apparent to those of ordinary skill in the art upon reading theforegoing description. The inventor expects skilled artisans to employsuch variations as appropriate, and the inventors intend for the presentinvention to be practiced otherwise than specifically described herein.Accordingly, this invention includes all modifications and equivalentsof the subject matter recited in the claims appended hereto as permittedby applicable law. Moreover, any combination of the above-describedembodiments in all possible variations thereof is encompassed by theinvention unless otherwise indicated herein or otherwise clearlycontradicted by context.

Groupings of alternative embodiments, elements, or steps of the presentinvention are not to be construed as limitations. Each group member maybe referred to and claimed individually or in any combination with othergroup members disclosed herein. It is anticipated that one or moremembers of a group may be included in, or deleted from, a group forreasons of convenience and/or patentability. When any such inclusion ordeletion occurs, the specification is deemed to contain the group asmodified, thus fulfilling the written description of all Markush groupsused in the appended claims.

Insubstantial changes from the claimed subject matter as viewed by aperson with ordinary skill in the art, now known or later devised, areexpressly contemplated as being equivalently within the scope of theclaims. Therefore, obvious substitutions now or later known to one withordinary skill in the art are defined to be within the scope of thedefined elements.

Unless otherwise indicated, all numbers expressing a characteristic,item, quantity, parameter, property, term, and so forth used in thepresent specification and claims are to be understood as being modifiedin all instances by the term “about.” As used herein, the term “about”means that the characteristic, item, quantity, parameter, property, orterm so qualified encompasses a range of plus or minus ten percent aboveand below the value of the stated characteristic, item, quantity,parameter, property, or term. Accordingly, unless indicated to thecontrary, the numerical parameters set forth in the specification andattached claims are approximations that may vary. For instance, as massspectrometry instruments can vary slightly in determining the mass of agiven analyte, the term “about” in the context of the mass of an ion orthe mass/charge ratio of an ion refers to +/−0.50 atomic mass unit. Atthe very least, and not as an attempt to limit the application of thedoctrine of equivalents to the scope of the claims, each numericalindication should at least be construed in light of the number ofreported significant digits and by applying ordinary roundingtechniques.

Notwithstanding that the numerical ranges and values setting forth thebroad scope of the invention are approximations, the numerical rangesand values set forth in the specific examples are reported as preciselyas possible. Any numerical range or value, however, inherently containscertain errors necessarily resulting from the standard deviation foundin their respective testing measurements. Recitation of numerical rangesof values herein is merely intended to serve as a shorthand method ofreferring individually to each separate numerical value falling withinthe range. Unless otherwise indicated herein, each individual value of anumerical range is incorporated into the present specification as if itwere individually recited herein.

Use of the terms “may” or “can” in reference to an embodiment or aspectof an embodiment also carries with it the alternative meaning of “maynot” or “cannot.” As such, if the present specification discloses thatan embodiment or an aspect of an embodiment may be or can be included aspart of the inventive subject matter, then the negative limitation orexclusionary proviso is also explicitly meant, meaning that anembodiment or an aspect of an embodiment may not be or cannot beincluded as part of the inventive subject matter. In a similar manner,use of the term “optionally” in reference to an embodiment or aspect ofan embodiment means that such embodiment or aspect of the embodiment maybe included as part of the inventive subject matter or may not beincluded as part of the inventive subject matter. Whether such anegative limitation or exclusionary proviso applies will be based onwhether the negative limitation or exclusionary proviso is recited inthe claimed subject matter.

The terms “a,” “an,” “the” and similar references used in the context ofdescribing the present invention (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. Further, ordinal indicators—such as, e.g., “first,” “second,”“third,” etc.—for identified elements are used to distinguish betweenthe elements, and do not indicate or imply a required or limited numberof such elements, and do not indicate a particular position or order ofsuch elements unless otherwise specifically stated. All methodsdescribed herein can be performed in any suitable order unless otherwiseindicated herein or otherwise clearly contradicted by context. The useof any and all examples or exemplary language (e.g., “such as”) providedherein is intended merely to better illuminate the present invention anddoes not pose a limitation on the scope of the invention otherwiseclaimed. No language in the present specification should be construed asindicating any non-claimed element essential to the practice of theinvention.

When used in the claims, whether as filed or added per amendment, theopen-ended transitional term “comprising”, variations thereof such as,e.g., “comprise” and “comprises”, and equivalent open-ended transitionalphrases thereof like “including,” “containing” and “having”, encompassall the expressly recited elements, limitations, steps, integers, and/orfeatures alone or in combination with unrecited subject matter; thenamed elements, limitations, steps, integers, and/or features areessential, but other unnamed elements, limitations, steps, integers,and/or features may be added and still form a construct within the scopeof the claim. Specific embodiments disclosed herein may be furtherlimited in the claims using the closed-ended transitional phrases“consisting of” or “consisting essentially of” (or variations thereofsuch as, e.g., “consist of”, “consists of”, “consist essentially of”,and “consists essentially of”) in lieu of or as an amendment for“comprising.” When used in the claims, whether as filed or added peramendment, the closed-ended transitional phrase “consisting of” excludesany element, limitation, step, integer, or feature not expressly recitedin the claims. The closed-ended transitional phrase “consistingessentially of” limits the scope of a claim to the expressly recitedelements, limitations, steps, integers, and/or features and any otherelements, limitations, steps, integers, and/or features that do notmaterially affect the basic and novel characteristic(s) of the claimedsubject matter. Thus, the meaning of the open-ended transitional phrase“comprising” is being defined as encompassing all the specificallyrecited elements, limitations, steps and/or features as well as anyoptional, additional unspecified ones. The meaning of the closed-endedtransitional phrase “consisting of” is being defined as only includingthose elements, limitations, steps, integers, and/or featuresspecifically recited in the claim, whereas the meaning of theclosed-ended transitional phrase “consisting essentially of” is beingdefined as only including those elements, limitations, steps, integers,and/or features specifically recited in the claim and those elements,limitations, steps, integers, and/or features that do not materiallyaffect the basic and novel characteristic(s) of the claimed subjectmatter. Therefore, the open-ended transitional phrase “comprising” (andequivalent open-ended transitional phrases thereof) includes within itsmeaning, as a limiting case, claimed subject matter specified by theclosed-ended transitional phrases “consisting of” or “consistingessentially of.” As such, the embodiments described herein or so claimedwith the phrase “comprising” expressly and unambiguously providedescription, enablement, and support for the phrases “consistingessentially of” and “consisting of.”

All patents, patent publications, and other references cited andidentified in the present specification are individually and expresslyincorporated herein by reference in their entirety for the purpose ofdescribing and disclosing, for example, the compositions andmethodologies described in such publications that might be used inconnection with the present invention. These publications are providedsolely for their disclosure prior to the filing date of the presentapplication. Nothing in this regard is or should be construed as anadmission that the inventors are not entitled to antedate suchdisclosure by virtue of prior invention or for any other reason. Allstatements as to the date or representation as to the contents of thesedocuments are based on the information available to the applicant and donot constitute any admission as to the correctness of the dates orcontents of these documents.

Lastly, the terminology used herein is for the purpose of describingparticular embodiments only and is not intended to limit the scope ofthe present invention, which is defined solely by the claims.Accordingly, the present invention is not limited to that precisely asshown and described.

1. A method of treating a schizophrenic disorder, the method comprisingadministering a combined therapy comprising one or more activators of analpha-7 nicotinic acetylcholine receptor activity having 5-HT₃ receptorinhibitory activity and one or more activators of 5-HT₃ receptoractivity.
 2. The method of claim 1, wherein the one or more activatorsof an alpha-7 nicotinic acetylcholine receptor activity comprise one ormore alpha-7 nicotinic acetylcholine receptor agonists, one or morepositive allosteric modulators of an alpha-7 nicotinic acetylcholinereceptor activity, or a combination thereof.
 3. The method of claim 2,wherein the one or more alpha-7 nicotinic acetylcholine receptoragonists include(+)-N-(1-azabicyclo[2.2.2]oct-3-yl)benzo[b]furan-2-carboxamide,A-582941, Acetylcholine, Amyloid beta, Anabasine, AR-R17779,Bradanicline, Choline, Encenicline, Epiboxidine, GTS-21, ICH-3,Nicotine, PHA-543,613, PHA-709829, PNU-282,987, SSR-180,711, TC-1698,Tilorone, Tropisetron, WAY-317,538, or any combination thereof.
 4. Themethod of claim 1, wherein the 5-HT₃ receptor inhibitory activitycomprise a 5-HT₃ receptor antagonistic activity, a 5-HT₃ receptorinverse agonistic activity, or a combination thereof.
 5. The method ofclaim 1, wherein the one or more activators of 5-HT₃ receptor activitycomprise one or more 5-HT₃ receptor agonists.
 6. The method of claim 5,wherein the one or more 5-HT₃ receptor agonists also have an alpha-7nicotinic acetylcholine receptor agonistic activity.
 7. The method ofclaim 5, wherein the one or more 5-HT₃ receptor agonists is an alcoholhaving 5-HT₃ receptor agonist activity, meta-Chlorophenylbiguanide(1-(3-Chlorophenylbiguanide)), Ibogaine, Phenylbiguanide, a piperazinehaving 5-HT₃ receptor agonist activity, RS-56812(N-(1-Azabicyclo[2.2.2]octan-3-yl)-2-(1-methylindol-3-yl)-2-oxoacetamide),Serotonin, SR-57227 (1-(6-Chloropyridin-2-yl)piperidin-4-amine),SR-57227A (4-Amino-1-(6-chloro-2-pyridyl)-piperidine hydrochloride), atryptamine having 5-HT₃ receptor agonist activity, Varenicline, avolatile gas having 5-HT₃ receptor agonist activity, and YM-31636(2-(1H-imidazol-4-ylmethyl)-8H-indeno[1,2-d]thiazole).
 8. The method ofclaim 1, wherein the one or more activators of an alpha-7 nicotinicacetylcholine receptor activity and the one or more activators of 5-HT₃receptor activity are provided in a therapeutic effective amount.
 9. Themethod of claim 2, wherein the one or more alpha-7 nicotinicacetylcholine receptor agonists, one or more positive allostericmodulators of an alpha-7 nicotinic acetylcholine receptor activityand/or the one or more 5-HT₃ receptor agonists are provided in atherapeutic effective amount.
 10. The method of claim 8, wherein thetherapeutic effective amount is a suboptimal therapeutic amount of theone or more alpha-7 nicotinic acetylcholine receptor agonists whenadministered alone, one or more positive allosteric modulators of analpha-7 nicotinic acetylcholine receptor activity when administeredalone and/or the one or more 5-HT₃ receptor agonists when administeredalone.
 11. The method of claim 1, wherein the one or more activators ofan alpha-7 nicotinic acetylcholine receptor activity is Tropisetron andthe one or more activators of 5-HT₃ receptor activity is Varenicline.12. The method of claim 11, wherein Tropisetron and Varenicline areprovided in a therapeutic effective amount.
 13. The method of claim 12,wherein the therapeutic effective amount of Tropisetron and Vareniclineis one where the amount of Tropisetron is a suboptimal therapeuticamount when administered alone and the amount of Varenicline is asuboptimal therapeutic amount when administered alone.
 14. The method ofclaim 2, wherein the one or more alpha-7 nicotinic acetylcholinereceptor agonists is Tropisetron and the one or more 5-HT₃ receptoragonists is Varenicline.
 15. The method of claim 14, wherein Tropisetronand Varenicline are provided in a therapeutic effective amount.
 16. Themethod of claim 15, wherein the therapeutic effective amount ofTropisetron and Varenicline is one where the amount of Tropisetron is asuboptimal therapeutic amount when administered alone and the amount ofVarenicline is a suboptimal therapeutic amount when administered alone.17. The method of claim 1, wherein the combination therapy comprisesadministration of a first composition comprising one or more activatorsof an alpha-7 nicotinic acetylcholine receptor activity and a secondcomposition comprising one or more activators of 5-HT₃ receptoractivity.
 18. The method of claim 1, wherein the combination therapycomprises administration of a single composition comprising one or moreactivators of an alpha-7 nicotinic acetylcholine receptor activity andone or more activators of 5-HT₃ receptor activity.
 19. The method ofclaim 2, wherein the combination therapy comprises administration of afirst composition comprising one or more alpha-7 nicotinic acetylcholinereceptor agonists and/or one or more positive allosteric modulators ofan alpha-7 nicotinic acetylcholine receptor activity and a secondcomposition comprising one or more 5-HT₃ receptor agonists.
 20. Themethod of claim 2, wherein the combination therapy comprisesadministration of a single composition comprising one or more alpha-7nicotinic acetylcholine receptor agonists and/or one or more positiveallosteric modulators of an alpha-7 nicotinic acetylcholine receptoractivity and one or more 5-HT₃ receptor agonists. 21-52. (canceled)